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Antibiotics Reduce the Efficacy of Immune Checkpoint Inhibitors in RCC, NSCLC

Jason Harris
Published Online:1:47 PM, Thu May 3, 2018
blood cells Antibiotics administered within 30 days of initiating treatment with PD-1 and PD­-L1 inhibitors were associated with poorer survival and increased risk for disease progression in patients with renal cell carcinoma (RCC) or non-small cell lung cancer (NSCLC).

Investigators have updated and reanalyzed previously reported findings to conduct a multivariate analysis. Data from 121 patients with advanced RCC treated at Gustave Roussy Cancer Campus in Villejuif, France, and 239 with NSCLC treated at Memorial Sloan Kettering Cancer Center were included in the results. Sixteen (13%) patients in the RCC group and 48 (20%) in the NSCLC group received antibiotics within the specified time frame.

Compared with patients with RCC who did not receive antibiotics within 30 days of treatment initiation, patients who received antibiotics had poorer median overall survival (OS; 17.3 vs 30.6 months; HR, 3.5; 95% CI, 1.1-10.8; P = .03), shorter median progression-free survival (PFS; 1.9 vs 7.4 months; HR, 3.1; 95% CI, 1.4-6.9; P <.01), and increased rate of primary progressive disease (75% vs 22%; P <.01).

Patients with NSCLC who received antibiotics within 30 days also had shorter median OS (7.9 vs 24.6 months; HR, 4.4; 95% CI, 2.6-7.7; P <.01) and shorter median PFS (1.9 vs 3.8 months; HR, 1.5; 95% CI, 1.0-2.2; P = .03). Rates of primary progressive disease were similar for patients who received antibiotics and those who did not (52% vs 43%; P = .26).

The effect remained significant for PFS in RCC (HR, 2.0; P <.01) and OS in NSCLC (HR, 2.5; 1.6-3.7; P <.01) in multivariate analysis that accounted for relevant prognostic factors. 

In the RCC cohort, 88% of patients received anti-PD­–1 or anti-PD–L1 monotherapy. The remaining patients received anti-PD­–1 or anti-PD–L1 in combination with anti-CTLA–4 (8%) or bevacizumab (Avastin; 4%). In the NSCLC cohort, patients received anti-PD­–1 or anti-PD–L1 alone (86%) or in combination with anti-CTLA–4 (14%).

Roughly a third of patients in the NSCLC cohort and 82% in the RCC cohort received β-lactams ± inhibitors, usually for pneumonia or urinary tract infections. Patients with NSCLC were also frequently prescribed quinolones and sulfonamides.

Investigators hypothesized that antibiotics can cause dysbiosis by altering gut microbiota diversity and composition, thereby reducing the efficacy of immune checkpoint inhibitor therapy.

“Altogether, these results confirm that [antibiotics]-associated dysbiosis might be deleterious in patients treated with [immune checkpoint inhibitors], suggesting that an intact gut microbiota is needed to mobilize the immune system regardless of the tumor site,” corresponding author Bertrand Routy, MD, PhD, Centre de recherche du Centre hospitalier de l’Université de Montréal, Montréal, Canada, wrote.

“Efforts to improve antibiotic stewardship are already ongoing to prevent the emergence of multidrug resistant organisms, which can be particularly dangerous for cancer patients,” investigators added. “The data in this report may add additional incentive to avoid unnecessary [antibiotics].”

Routy et al also examined the effect of antibiotics within 60 days of initiating therapy to test the strength of the findings. Twenty-two (18%) patients with RCC and 68 (28%) with NSCLC were included in this analysis.

In the RCC cohort, investigators observed an association between antibiotics administered within 60 days and poorer median PFS (3.1 vs 7.4 months; HR, 2.3, 95% CI, 1.2-4.4; P <.01) and increased risk for primary progression (P <.01). There was also a trend towards poorer median OS (23.4 vs 30 months; HR, 1.9; 95% CI, 0.8-4.7; P =.15).

Investigators found that objective response and PFS were similar between patients in the NSCLC cohort who received antibiotics within 60 days and those who did not. However, there was still a significant association between antibiotics within 60 days and poorer median OS (9.8 vs 21.9 months; HR, 2.0; 95% CI, 1.3-3.2; P <.01).
Derosa L, Hellmann MD, Spaziano M, et al. Negative association of antibiotics on clinical activity of immune checkpoint inhibitors in patients with advanced renal cell and non-small cell lung cancer [published online March 30, 2018]. Ann Oncol. doi: 10.1093/annonc/mdy103.

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