Background:
Preclinical data demonstrated that microbiota modulates activity of immune checkpoint inhibitors (ICB) and broad-spectrum antibiotics (ATB) damper their efficacy. However, the impact of ATB in patients (pts) treated with ICB remains unknown. Our study evaluates the effect of ATB use in metastatic renal cell carcinoma (mRCC) pts treated with ICB.
Methods:
We conducted a retrospective analysis of mRCC pts treated in prospective trials at Gustave Roussy with PD1/PD-L1 inhibitors alone or in combination. ATB (+)/(-) group were defined as pts treated or not with ATB at baseline (up to 1 month prior to the 1st injection of ICB). Progression-Free survival (PFS), Objective Response Rate (ORR), and Overall Survival (OS) were compared in each group (ATB (+) vs ATB (-)). Statistical analyses were performed using Kaplan-Meier method and Cox regression adjusted for risk factors.
Results:
We enrolled 80 mRCC pts treated with anti-PD-1/PD-L1 monotherapy (n=67), anti-PD-1 plus CTLA-4 (n=10) or anti-PD-L1 plus bevacizumab (n=3) with available data on ATB. Majority of pts were male (65%), clear-cell histology (88%), and had prior nephrectomy (80%). With regard to IMDC risk groups, 21%, 57%, and 22% had favorable, intermediate, and poor-risk disease, respectively. Sixteen (20%) pts belonged to the ATB (+) group (mostly receiving beta-lactamases and fluoroquinolones). ATB (+) had decreased PFS compared to ATB (-), 2.3 vs. 8.1 months, p<0.001. This statistical association was maintained after multivariate analysis adjusted for age, gender, IMDC risk groups, tumour burden and proton pomp inhibitors. In addition, ORR was lower in ATB (+) compared with ATB (-) (p<0.002). Even though it is too early to conclude on OS (median follow-up <6 months), there was already a negative trend driven in ATB (+).
Conclusions:
This is the first analysis evaluating the impact of ATB in mRCC pts treated in the era of ICB. Recent use of ATB prior to ICB, negatively influences responses even after multivariable analysis for prognostic risk factors. Further studies are warranted to investigate whether the alteration of gut microbiota compositions is responsible for this different outcome.
This retrospective analysis suggests efficacy of immunotherapy may be lower in patients receiving antibiotic less than a month before starting treatment. Relationship between the gut microbiome and response to immunotherapy should be further investigated.