Acetaminophen May Hinder Immunotherapy Efficacy in Cancer

Immune checkpoint inhibitors (ICIs) have changed the paradigm of cancer treatment, and indications for their use are expanding. In addition to specific systemic therapy such as ICIs, many patients require treatment for cancer-related symptoms, such as pain, during the course of their disease. Acetaminophen (APAP, or paracetamol) alone, or in combination with other analgesics, is commonly used for cancer-related pain. APAP is generally considered to be safe, but emerging evidence suggests that it may have negative immunomodulatory effects. For instance, APAP use has been associated with decreased antibody response to vaccination. At ASCO’s 2022 annual meeting, interesting data assessing the impact of APAP on immunotherapy efficacy in patients with cancer were presented. These data, and an accompanying editorial, were recently also published in the Annals of Oncology.

Investigators evaluated the effects of APAP exposure on clinical outcomes by analyzing serum/plasma metabolomics data from three independent cohorts of patients with advanced cancer who received ICIs. Patients from CheckMate 025 and two French institutional biomarker programs, BIP and PREMIS were included. In the CheckMate 025 cohort (n=297), detection of APAP or its metabolite APAP glucuronide at immunotherapy onset was associated with worse overall survival (OS) compared with those without detectable levels (Hazard Ratio [HR] 0.67; P=0.004). In the BIP cohort (n=34), those with detectable APAP or its metabolite had significantly worse objective response (ORR; 0% vs 29.4%; P=0.015) and a trend towards worse median progression free survival (PFS) and OS. Patients from the PREMIS study (n=297) had significantly worse PFS (HR 0.69; P=0.009) and OS (HR 0.47; P<0.001). Furthermore, multivariate analysis from this cohort showed that the presence of APAP (or its metabolite) was associated with worse PFS and OS independently of other prognostic factors, including age, tumor type, ECOG performance status, liver metastases, and LDH levels. In line with these clinical findings, investigators demonstrated that APAP also reduced the efficacy of ICIs in a preclinical mouse model of colorectal cancer (MC38) that is known to respond well to ICIs. Mice tumors treated with APAP plus ICI showed increased regulatory T-cells (Tregs) infiltration and reduced interferon-γ secretion. Similar immunomodulation effects of APAP were shown in an analysis of peripheral blood mononuclear cells (PBMC) in healthy volunteers who received APAP over a period of 24-hours. Presenter Antoine Italiano, MD (Institut Bergonié, Bordeaux, France) concluded that these preclinical and clinical data indicate that APAP is associated with decreased efficacy of ICIs in patients with advanced cancer and should be used with caution, although more research is needed.

In her discussion, Margaret Gatti-Mays, MD, MPH (The Ohio State University, Columbus, Ohio, USA) commented that commonly used medications may have a larger impact on the efficacy and toxicity of ICIs than has been reported historically with chemotherapy. Thus, clinicians need to consider more than just drug-drug interactions, and have a better understanding the off-target effects on the tumor microenvironment, peripheral immune response, and normal flora. She called the data ‘’hypothesis-generating’’, and not yet practice changing. She raised questions around the pharmacokinetics of APAP exposure and the true impact on ICI efficacy, especially given its shorter half-life (1 – 3 hours) compared to ICIs (20 – 25 days, with PD-L1 occupancy exceeding 100 days). She also questioned whether chronic analgesic use (e.g., with APAP) may be ‘’a surrogate for more advanced malignancy.’’

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