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Common rheumatologic drugs may impede checkpoint inhibitor efficacy
ATLANTA — Drugs that have known potential impacts on gut microbiota and are commonly prescribed by rheumatologists can have detrimental impacts on the efficacy of immune checkpoint inhibitors used to treat cancer, according to data presented at the ACR/ARP 2019 Annual Meeting.
“The composition of microbiota seems to play in the response to ICIs,” Thierry Schaeverbeke, PhD, of the Hospital Pellegrin, of Bordeaux, France, told attendees. “Secondly, it has recently been shown that antibiotic treatment given at the initiation of ICI therapy had a dramatic impact on microbiota that compromised the anti-tumoral effect of ICIs. A previous study found that withholding antibiotic treatment two months before the introduction of anti-PD1 should improve the response rate from 25% to 40%, which is not nothing.”
“So, when we reviewed this paper, we considered that antibiotics are not the only treatment with impacts on the microbiota,” he added. “There are a lot of treatments that have an important impact on microbiota, and the idea was to look for treatments that are most commonly used in our patients, and to look if these treatments do impact the results of the anti-PD1 treatments.”
To determine whether medications known to have potential effects on gut microbiota have an impact on the efficacy of immune checkpoint inhibitors, or the occurrence of immune-related adverse events, Schaeverbeke and colleagues conducted a retrospective cohort study. The researchers included 635 patients with cancer who received immune checkpoint inhibitors at the Hospital Center University of Bordeaux from May 2015 to September 2017. Among them, 293 had melanoma, 150 had advanced non-small cell lung cancer and 83 had renal carcinoma.
Medications prescribed to patients within 1 month — either before or after — of initiating immune checkpoint inhibitors were analyzed based on a predefined list of drugs known to impact gut microbiota. Each participant was regularly evaluated for tumor response, immune-related adverse events and outcomes. Overall survival was considered from the start of immune checkpoint therapy.
Among the included participants, 8% demonstrated a previous autoimmune disorder — mainly rheumatic and endocrine diseases. The most common medications coprescribed alongside immune checkpoint inhibitors were psychotropic drugs, which were used by 41.1% of participants; proton pump inhibitors, 37.3%; angiotensin-converting enzyme (ACE) inhibitors or angiotensin II receptor blockers (ARB), 32%; glucocorticoids, 24.2%; antibiotics, 21.4%; statins, 20.8%; and morphine, 20.6%.
According to the researchers, baseline use of glucocorticoids, at 10 mg or more of prednisone equivalent, was associated with a significant decreased overall survival (median 4.5 months vs. 24.3 months; P < .0001) as well as less frequent tumor response (55% vs. 73%; P = .0001). However, when prescribed for the management of immune-related adverse events following the checkpoint therapy initiation, glucocorticoids did not impact efficacy.
Baseline use of proton pump inhibitors also impeded overall survival (median 10.9 months vs. 24.3 months; P < .0001) and tumor response (62% vs. 71%; P = .02). The researchers also determined that antibiotics, when given at checkpoint therapy initiation, resulted in a detrimental impact on efficacy, as well as worse outcomes for patients receiving baseline psychotropic drugs (P = .0001). There were no significant impacts related to baseline use of NSAIDs, aspirin, statins, ACE inhibitors and ARBs.
The use of antibiotics, glucocorticoids, proton pump inhibitors, morphine, NSAIDs, aspirin and psychotropic drugs, when taken alongside checkpoint therapy, was associated with a decreased occurrence of immune-related adverse events.
“Rheumatologists and oncologists should be aware of the potential detrimental effect of some co-medications when used at ICI initiation,” Schaeverbeke said. “This includes antibiotics, baseline glucocorticoids in doses of more than 10 mg/d, proton pump inhibitors and psychotropic drugs. In our patients, some of these — maybe at least half of them — could have been avoided, especially proton pump inhibitors. Interestingly, the same co-medications are associated with a decreased incidence of immune-related adverse effects. However, the demonstration that this effect is related to gut microbiota was not possible with our study, but needs to be done.” – by Jason Laday
Reference:
Kostine M. Abstract #1811. Commonly used drugs in rheumatology may alter anti-tumoral response to immune checkpoint inhibitors. Presented at: American College of Rheumatology/Association of Rheumatology Professionals Annual Meeting; Nov. 9-13, 2019; Atlanta.
Disclosure: Schaeverbeke reports professional relationships with Bristol Myers Squibb, Janssen, Eli Lilly, Nordic Pharma, Novartis, Pfizer, Roche Chugai and Sanofi.