Immunotherapy is less effective when given shortly after antibiotics
BY SUSAN LONDON
Antibiotic therapy may alter the gut microbiota in a way that reduces the effectiveness of immune checkpoint inhibitors, according to a retrospective cohort study of patients with advanced renal cell carcinoma (RCC) or non–small cell lung cancer (NSCLC).
Receipt of antibiotics in the 30 days before starting immunotherapy with antibodies that target programmed cell death protein 1 (PD-1) or programmed death ligand 1 (PD-L1) was associated with poorer disease outcomes,
according to data reported in the Annals of Oncology. In particular, receipt was associated with a doubling of the adjusted risk of progression or death among patients with RCC and a more than doubling of the adjusted risk of death among patients with NSCLC.
Findings were similar in subgroup analyses but were somewhat attenuated when the window for antibiotic exposure was extended out to 60 days before the start of the immune checkpoint inhibitor.
“Altogether, these results confirm that [antibiotic]-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,” the investigators contended.
On the other hand, they noted, “Modulation of [antibiotic]-related dysbiosis and gut microbiota composition may be a strategy to improve clinical outcomes with [immune checkpoint inhibitors].”
Investigators led by Lisa Derosa, MD, of the Gustave Roussy Cancer Campus in Villejuif, France, studied 121 patients with advanced RCC from Gustave Roussy and 239 patients with advanced NSCLC from the Memorial Sloan Kettering Cancer Center receiving an immune checkpoint inhibitor, usually as monotherapy but sometimes in combination with bevacizumab or another immunotherapy.
A review of medical records indicated that 13% of the former patients and 20% of the latter received oral or intravenous antibiotics in the 30 days before starting immunotherapy. Most commonly, they received beta-lactam or quinolone antibiotics for pneumonia or urinary tract infections.
Within the RCC group, patients with antibiotic exposure were more likely than nonexposed peers to have primary progressive disease
(75% vs. 22%; P less than .01) and had shorter median progression-free survival (1.9 vs. 7.4 months; hazard ratio, 3.1; P less than .01) and overall survival (17.3 vs. 30.6 months; HR, 3.5; P = .03).
Within the NSCLC group, those exposed to antibiotics were likely to have similar rates primary progressive disease as their nonexposed peers (52% vs. 43%, P = .26), but they had shorter median progression-free survival (1.9 vs. 3.8 months; HR, 1.5; P = .03) and overall survival (7.9 vs. 24.6 months; HR, 4.4; P less than .01).
In multivariate analyses, antibiotic exposure was still associated with poorer progression-free survival in RCC (HR, 2.0; P less than .01) and poorer overall survival in NSCLC (HR, 2.5; P less than .01).
The study did not assess antibiotic-related changes in gut microbiota or the effects of antibiotic therapy on immune-related adverse events, the investigators acknowledged.
“More studies are warranted to confirm the deleterious effect of [antibiotics] in large prospective trials and to develop novel diagnostic tools based on gut microbiota in cancer patients to predict response/resistance to [immune checkpoint inhibitors] and identify the key microbiota signatures for each tumor site,” they concluded. “The discovery of bacteria capable of shifting an unfavorable [antibiotic]-associated dysbiosis to a favorable microbiota will help build a future therapeutic concept whereby modulation of gut microbiota by bacteria could increase [immune checkpoint inhibitor] clinical activity.”