medwireNews: French researchers have identified an association between detectable plasma levels of acetaminophen (paracetamol) and poor outcomes in people receiving immune checkpoint inhibitors (ICIs) for advanced cancer.
“Our results confirm that more research should be performed to understand the impact of [acetaminophen] on immunity and present a compelling case for caution in using this drug in cancer patients treated with [ICIs],” they write in the Annals of Oncology publication accompanying the study presentation at the 2022 ASCO Annual Meeting in Chicago, Illinois, USA.
But further investigation is needed to determine whether this caution applies at the initiation of immunotherapy or throughout the treatment duration, whether it applies to just acetaminophen or all antipyretics, and to all ICI regimens or to other immuno-oncology agents, the team adds.
Outlining the rationale for the study, Antoine Italiano (Gustave Roussy, Villejuif) and co-authors explain that “[a]lthough generally considered to be safe, evidence suggests that [acetaminophen] may have negative immunomodulatory effects.”
They therefore analyzed publicly available serum metabolomics data from 297 nivolumab-treated participants of the CheckMate 025 advanced renal cell carcinoma trial, and found that overall survival (OS) was significantly worse for those with versus without detectable levels at treatment initiation of acetaminophen or its metabolite acetaminophen glucuronide (hazard ratio [HR]=0.67).
The researchers also applied an untargeted mass spectrometry-based metabolomics approach to plasma samples from 34 ICI-treated individuals included in the BIP study and a quantitative mass spectrometry approach to samples from 297 ICI-treated participants of the PREMIS study. The median age of the PREMIS participants was 63 years and the most common tumor type was non-small-cell lung cancer (37.4%).
Once again, the presence of detectable levels of acetaminophen at baseline was associated with worse ICI therapy outcomes. For instance, in the BIP participants, none of those exposed to acetaminophen achieved an objective response compared with 29.4% of those not exposed to the drug, a significant difference.
And in PREMIS, both progression-free survival (PFS) and OS were significantly poorer for participants with detectable acetaminophen than those without, at medians of 2.63 versus 5.03 months and 8.43 versus 14.93 months, respectively, and corresponding HRs of 0.69 and 0.47.
In a multivariate analysis based on the PREMIS data, acetaminophen exposure was independently and significantly associated with worse PFS and OS (HRs=1.43 and 1.78, respectively) after adjusting for known confounders such as age, lactate dehydrogenase levels, and presence of liver metastases.
These results were supported by a raft of in vivo and laboratory data, which also provided insights into the mechanisms underlying the immunomodulatory effects of acetaminophen. For example, in the MC38 mouse model of colon cancer, the efficacy of anti-PD-1 pathway agents was reduced when acetaminophen was administered concomitantly.
And immunophenotyping of peripheral blood mononuclear cells from four cancer-free individuals who took 1000 mg of acetaminophen every 6 hours for a 24-hour period showed an expansion of regulatory T cells (Tregs) and increased expression of the co-inhibitory receptors LAG3 and TIM3, “which are associated with a strong immunosuppressive phenotype,” say Italiano and colleagues.
They continue: “Altogether, our data suggest that Tregs are key players that may underlie the immunomodulatory effect of [acetaminophen], thus compromising [ICI] efficacy.”
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