ASCO GU 2018: Antibiotic Use and Outcomes with Systemic Therapy in Metastatic Renal Cell Carcinoma (mRCC)
The authors note that, in recent past, there is increasing evidence of that an individual’s gut biome has an important regulatory effect on immune homeostasis. There, as antibiotic use has been shown to affect commensal gut microbiota, they hypothesized that antibiotic use may impact the efficacy of systemic therapy in mRCC. They conducted the largest study to date in this field. It was a retrospective institutional series as well as a review of pooled clinical trial data.
Two cohorts were analyzed
1) an institutional cohort (Dana Farber, DFCI, n = 146) of patients receiving PD-1/PD-L1-based immune checkpoint inhibitors (ICI)
2) external cohort from pooled phase II/III clinical trials (Pfizer, n = 4144) of patients treated with interferon (IFN, n = 510), mTOR inhibitors (n = 660), and VEGF inhibitors (n = 2974)
Antibiotic use was defined as antibiotic treatment at any time between 8-weeks pre- and 4-weeks post the start of systemic therapy. We examined the associations of antibiotic use and objective response rate (ORR), progression-free survival (PFS), and overall survival (OS) using Cox/logistic regression models, adjusted for prognostic factors including risk groups.
In the DFCI cohort, 15% had non-clear cell histology, 43% had first-line ICI, 45% had combination therapy. Baseline characteristics were balanced between antibiotic users (n = 31, 21%) and non-users (n=115, 79%) (p > 0.15). However, it should be noted that non-used has a higher rate of non-clear cell RCC, higher presence of sarcomatoid features, and higher rate of intermediate risk but lower rate of high-risk patients. Antibiotics were predominantly beta-lactams and fluoroquinolones. Antibiotic users had a lower ORR (12.9 vs 34.8%, p = 0.026) and shorter PFS compared to non-users. There was no difference in OS.
In the external cohort, the groups were relatively well matched. Antibiotics were predominantly beta-lactams and fluoroquinolones. Abx users (n = 709, 17.1%) had a lower ORR (19.3 vs 24.2%, p = 0.005) than non-users (n=3435, 82.9%). IFN treated patients (current or prior cytokines) had worse OS if they received Abx compared to those who did not. However, there was no OS difference by Abx use in mTOR or VEGF treated patients without prior cytokines.
Based on this, the authors note that Abx use was independently associated with worse outcomes in mRCC patients receiving contemporary ICI or historic cytokine immunotherapy. They hypothesize that concurrent use of Abx may reduce the efficacy of ICI due to a complex interplay with the host microbiome.
While there may be association here, causation is not yet clear. The changes identified may be due to many other reasons, including direct interaction between Abx and drug, immunosuppression effects of abx, abx being given for a side-effect of treatment leading to drug dose reduction/discontinuation, etc. Prospective randomized studies are needed, with prospective evaluation of the gut flora.
Regardless, this is an interesting study that warrants further investigation.!
Limitations / Discussion Points:
1. Antibiotic duration and indication was not detailed.
2. High risk of confounders, inherent to a retrospective series.
Speaker: Aly-Khan Lalani, MD, FRCPC
Co-Authors: Wanling Xie, Xun Lin, John A. Steinharter, Dylan J. Martini, Audrey Duquette, Dominick Bosse, Rana R. McKay, Ronit Simantov, Xiao X. Wei, Bradley A McGregor, Lauren Christine Harshman, Toni K. Choueiri
Institution(s): Dana-Farber Cancer Institute, Boston, MA; Pfizer Oncology Inc., San Diego, CA; University of California San Diego, San Diego, CA; Pfizer Oncology Inc., New York, NY; Dana-Farber Cancer Institute/ Brigham and Women’s Hospital/ Harvard Medical School, Boston, MA
Written by: Thenappan Chandrasekar, MD, Clinical Fellow, University of Toronto, Twitter: @tchandra_uromd at the 2018 American Society of Clinical Oncology Genitourinary (ASCO GU) Cancers Symposium, February 8-10, 2018 - San Francisco, CA