Antibiotics reduce checkpoint inhibitor efficacy

Antibiotics should be avoided where possible in patients receiving checkpoint inhibitor therapy, according to US researchers who found their use was associated with reduced overall survival (OS) in melanoma patients.

In what they say is further evidence of the influence of the microbiome on outcomes with immune checkpoint inhibitors, researchers from the University of Pennsylvania found that antibiotic use in the three months prior to starting therapy was associated with a significantly worse OS in patients with stage III disease (hazard ratio 2.78) and stage IV disease  (HR 1.81).

The findings, published in the Journal of the National Cancer Institute are based on a retrospective analysis of outcomes in 568 patients with melanoma treated with checkpoint inhibitors, of whom 114 received antibiotics prior to therapy.

Among all patients, median survival was significantly longer among the antibiotic-unexposed patients compared to antibiotic-exposed patients (43.7 vs. 27.4 months).

The detrimental effect of antibiotics appeared to be greater in patients with better prognosis, such as those with non-metastatic melanoma receiving checkpoint inhibitors as adjuvant therapy, in whom there was a Hazard Ratio of 4.84 for antibiotic use on reduced overall survival.

The association of antibiotic use with reduced overall survival and melanoma-related survival was seen after adjustment for variable such as stage, ECOG, gender, age, prior targeted therapy, LDH, and BRAF mutation status. It was also still evident when the analysis was confined to patients who had minor infections (ie excluding intravenous antibiotics) and in patients who received antibiotics for a shorter window of 45 days.

The study also showed that antibiotic-exposed patients had a greater incidence of moderate to severe immune-mediated colitis (HR 2.14 compared to unexposed patients), but that steroid use was not related to the effect on OS.

The researchers said the findings supported the hypothesis that higher microbiome diversity and certain commensal bacteria are associated with an improved response to checkpoint inhibitors.

And the novel finding that the detrimental effect of antibiotics was greater in patients with a better-prognosis, “suggests that antibiotic-induced dysbiosis could mean the difference between long-term cure and metastatic recurrence in high-risk Stage III patients,” they said.

Since other studies had shown that up to 30% of antibiotic therapy is inappropriate, they said there is a need to be prudent with antibiotic use in cancer patients.

“These findings are particularly relevant for patients undergoing surgery for stage III or IV melanoma, in whom adjuvant immune checkpoint inhibitor therapy is planned, as injudicious antibiotic use in the post-operative setting should be avoided if possible,” they wrote.

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