Acetaminophen Linked to Diminished Response to Immunotherapy in Cancer

French investigators are warning about using acetaminophen in patients with cancer who are taking immune checkpoint blockers.

The team found a strong association between the use of acetaminophen and a decreased response to immune checkpoint inhibitors in a study of three clinical cohorts involving more than 600 patients with advanced cancer.

Patients who took acetaminophen at the start of immunotherapy — with acetaminophen exposure confirmed by plasma testing — were found to have worse overall survival and progression-free survival than patients who did not take the analgesic. Multivariate analysis confirmed the association independent of other prognostic factors. “It is unlikely that our data are the result of bias or unmeasured confounding,” the authors comment.

The findings “present a compelling case for caution” in using acetaminophen in patients with cancer who are receiving immune checkpoint blockers, senior investigator Antoine Italiano, MD, PhD, a medical oncologist at the University of Bordeaux, France, and colleagues concluded.

The study was presented at the American Society of Clinical Oncology annual meeting and published simultaneously in the Annals of Oncology.

“Patients with advanced cancer taking [acetaminophen] during immunotherapy experience worse clinical outcomes, which suggests that [acetaminophen] decreases T cell-mediated antitumor immunity,” the authors comment.

They also report bench research and blood studies in four healthy volunteers, which showed an upregulation of immunosuppressive regulatory T cells (Tregs) with acetaminophen, and other findings that together suggest that acetaminophen undermines the antitumor immune processes by which checkpoint inhibitors work.

Reconsider Acetaminophen Pretreatment

After hearing Italiano present the results at the meeting, a Polish oncologist in the audience said he was concerned that his clinic premedicates with acetaminophen before immune checkpoint blockade and wanted to know if they should stop doing it.

“I don’t think inducing Tregs…in cancer patients is a good approach. I do a lot of clinical trials,” and “I do not understand why in several cases sponsors required mandatory premedication with acetaminophen. I think…we should reconsider this approach,” Italiano said.

There’s precedence for the findings. Acetaminophen — also known as paracetamol — has been shown in some studies to limit immune cell proliferation, T-cell–dependent antibody response, and viral clearance, among other things. After a randomized trial showing blunted responses to vaccines in individuals who were taking acetaminophen, the World Health Organization recommended in 2015 against concurrent use of acetaminophen with vaccines.

Steroids, antibiotics, and proton pump inhibitors have also recently been shown to worsen outcomes with pembrolizumab, noted invited discussant, Margaret Gatti-Mays, MD, a medical oncologist at Ohio State University, Columbus.

“We are starting to understand that…commonly used medications may have a larger impact on the efficacy and toxicity of immune checkpoint blockade than historically seen with chemotherapy,” she said.

However, she expressed some uncertainty over the French findings, as she was concerned that even the multivariate analysis didn’t completely rule out that acetaminophen users had worse disease to begin with and so would be expected to have worse outcomes.

She was also unsure of how much acetaminophen is too much.

Acetaminophen has a half-life of around 3 hours or less, where the immune checkpoint inhibitors have a half-life of around 20 days or more.

Given that, Gatti-Mays wondered whether “a single dose of acetaminophen [is] enough to derail the benefit of checkpoint inhibition? Does exposure need to be continuous?”

She allowed that acetaminophen use may turn out to be one more of the many patient-level factors emerging lately — such as chronic stress, diet, body flora, and physiologic age, among others — that might help explain why checkpoint inhibition works in only about 20% of eligible patients with cancer.

Study Details

Italiano and his team analyzed plasma samples from 297 participants in the CheckMate 025 trial of nivolumab for renal cancer; 34 participants in the BIP study into actionable molecular alterations in cancer; and 297 participants in the PREMIS immune-related adverse events study. The patients in these last two studies had a variety of cancers and were taking various agents.

All 628 patients were on checkpoint inhibitors. The investigators divided them according to who had acetaminophen or its metabolite acetaminophen glucuronide in their plasma when they started checkpoint inhibition and those who did not.

In CheckMate 025, overall survival was significantly worse among participants who had detectable acetaminophen or its metabolite in plasma (hazard ratio [HR], 0.67; P = .004).

None of the acetaminophen-positive participants in the BIP study responded to checkpoint blockade, compared with almost 30% of those who were negative. Acetaminophen-positive participants also trended toward worse progression-free survival (median, 1.87 vs 4.72 months) and overall survival (median, 7.87 vs 16.56 months).

In PREMIS, progression-free survival was a median of 2.63 months in the acetaminophen group vs 5.03 months in negative participants (P = .009); median overall survival was 8.43 months vs 14.93 months, respectively (P < .0001).

A multivariate analysis was performed in PREMIS. Acetaminophen exposure was associated with both progression-free survival (HR, 1.43; P =.015) and overall survival (HR, 1.78; P =.006) independently of performance status, liver metastases, bone metastases, number of metastases sites, tumor type, number of previous lines of treatment, steroid/antibiotic use, lactate dehydrogenase levels, and other factors.

There was no funding for the work. Italiano is a consultant for AstraZeneca, Bayer, Chugai, Deciphera, Merck, Parthenon, Roche, and Springworks, He also has grants from AstraZeneca, Bayer, BMS, Merck, MSD, Novartis, Pharmamar, and Roche. Two authors work for Explicyte and one works for Amgen. Gatti-Mays is a consultant for Seattle Genetics.

Annals of Surgery, published online 6 June

ASCO annual meeting abstract 12000 , presented 6 June

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 and is also an MIT Knight Science Journalism fellow. Email: [email protected]

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