Immune checkpoint inhibitors (ICIs) do not work as well if patients had been taking antibiotics even a year beforehand, conclude the authors of a review of almost 3000 older cancer patients in Ontario, Canada.
Any antibiotic exposure within a year of starting ICI treatment was associated with worse overall survival (aHR, 1.12; P = .03).
The findings were adjusted for comorbidity status, recent hospitalizations, and other factors to account for the most obvious potential confounder ― that patients were taking antibiotics in the first place because they were sicker to begin with and so were more likely to die sooner regardless of ICI therapy, researchers say.
“In this population-level study, antibiotic exposure and specifically fluoroquinolones before ICI therapy were observed to be associated with worse OS [overall survival], with fluoroquinolone exposure conferring up to a 65% increased risk of mortality among older adults with cancer,” say the investigators, led by Lawson Eng, MD, a medical oncologist at the University of Toronto.
“Interventions focused on limiting antibiotic exposure before ICI therapy, modifying or restoring the gut microbiome before starting [an] ICI, and sequencing non-ICI treatment options (if available) first in those recently exposed to antibiotics are warranted,” they conclude.
The study was published online on February 24 in the Journal of Clinical Oncology.
The likely reason for the association is that antibiotics induce changes in the gut microbiome that affect ICI effectiveness, the authors suggest. Although the mechanism remains illusive, past studies have shown that greater bacterial diversity and the presence of specific species/classes in the gut influence responses to ICIs, they explain.
In an accompanying editorial, two medical oncologists at Imperial College London describe the findings as “highly informative to clinical practice.”
The “key objective now is to demonstrate whether reversal of antibiotic-mediated gut dysbiosis might prove to be beneficial in abolishing [this] increasingly well-characterized mechanism of ICI resistance,” David Pinato, MD, PhD, and Alessio Cortellini, MD, PhD, say in their editorial.
Among many possible options, fecal transplant from immunotherapy-responsive donors seems promising. Switching patients who have been receiving antibiotics to chemoimmunotherapy combinations might also be helpful because combination therapy seems less sensitive to the effects of antibiotics, they say.
Study Details
For their study, Eng and colleagues analyzed prescription and healthcare databases in Ontario for 2737 patients aged 65 years or older who began taking an ICI between 2012 and 2018.
Lung cancer was the most common diagnosis (53%), followed by melanoma (34%) and renal and bladder cancers. Nivolumab and pembrolizumab were the most common initial ICIs. Median overall survival was 306 days after the start of an ICI.
Overall, 59% of patients filled at least one prescription for oral antibiotics in the year before starting immunotherapy, and 19% filled at least one prescription 60 days before.
The average antibiotic regime was 30 doses over 2 weeks among patients who filled a prescription within a year. The average number of doses was 21 over 1.3 weeks among those who started antibiotic therapy within 60 days. The specific infectious disease indications were not reported.
Fluoroquinolones emerged in the study as the antibiotic class most strongly associated with inferior survival within 1 year (aHR, 1.26; P < .001) and 60 days of starting an ICI (aHR, 1.20; P = .06).
A dose effect was seen with fluoroquinolones among patients with lung cancer or melanoma who received PD-1 inhibitors. Survival grew steadily worse with longer use (eg, aHR, 1.07 per week among patients who were taking antibiotics within a year of ICI initiation).
Fluoroquinolones, the study team notes, can alter levels of many gut microbiota, including Faecalibacterium, Ruminococcus, Bifidobacteria, and Alistipes, all of which have been found to affect ICI responses. Penicillins and cephalosporins had no influence on overall survival among patients taking PD-1 blockers.
Among contrary findings, there was no significant association between antibiotic exposure and overall survival among patients with renal cancer. Among patients who took the CTLA-4 blocker ipilimumab, overall survival was actually better with more antibiotic exposure in the preceding year (aHR, 0.92; P = .03).
The study was funded by the Ontario Ministry of Health and others. Eng has disclosed no relevant financial relationships. One co-author is an employee of GlaxoSmithKline, and three other investigators reported consulting/research/speakers ties to Pfizer, Merck, Lilly, and other companies. Pinato and Cortellini has ties to AstraZeneca, Roche, Bristol-Myers Squibb, and others.
J Clin Oncol. Published online February 24, 2023. Abstract, Editorial
M. Alexander Otto is a physician assistant with a master’s degree in medical science and a journalism degree from Newhouse. He is an award-winning medical journalist who worked for several major news outlets before joining Medscape. Alex is also an MIT Knight Science Journalism fellow. Email: [email protected]
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