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Patients starting cancer immunotherapy with detectable levels of acetaminophen had worse outcomes, including response rate, progression-free survival (PFS), and overall survival (OS), in data from three patient cohorts.

In the largest of the three studies (N=392), patients with detectable acetaminophen had a 33% lower likelihood of survival as compared with patients who did not have detectable acetaminophen at the start of treatment with nivolumab (Opdivo).

An analysis of 297 patients treated with a PD-1/L1 inhibitor (alone or in combination with a CTLA-4 inhibitor) showed about a 50% reduction in PFS and OS among patients with detectable acetaminophen. In the third study (N=34), no patient with detectable acetaminophen achieved an objective response, and both PFS and OS were numerically worse than in those without acetaminophen onboard.

Studies involving an animal model of colon cancer supported the clinical data, showing lower response rates with immunotherapy in animals pretreated with acetaminophen, reported Alban Bessede, PhD, of Explicyte, a preclinical research organization in Bordeaux, France, and coauthors, in the .

Together, the findings suggested that acetaminophen decreases T cell-mediated antitumor immunity in advanced cancer, the authors said. "It is unlikely that our data are the result of bias or unmeasured confounding."

"Our study reports the most comprehensive picture of the immunomodulatory effects of APAP [acetaminophen]," they added. "Our results confirm that more research should be performed to understand the impact of APAP on immunity and present a compelling case for caution in using this drug in cancer patients treated with ICB [immune checkpoint blockade]. Whether this rule applies at immunotherapy onset or all over the treatment duration, to all antipyretics, all regimens ... and to other immuno-oncology agents ... requires further investigations."

Compelling Evidence

As use of immuno-oncology approaches has increased, the potential for interaction with common medications has become a more relevant clinical issue, noted the authors of an on what they called "important, compelling, and concerning data" in the current study.

"In all, the data supports the conclusions that APAP appears to blunt ICI (immune checkpoint inhibitor) effectiveness, perhaps through activating regulatory immune elements, namely Tregs (regulatory T cells)," wrote Pedro Berraondo, PhD, of Cima Universidad de Navarra in Pamplona, Spain, and Ryan J. Sullivan, MD, of Mass General Cancer Center in Boston.

However, they noted: "The major weakness of this analysis is the potential for confounding. While the authors attempted to limit this by performing multivariate analysis and used data from three distinct clinical trials, it is hard to tease out the effect of the fact that patients treated with APAP may be those with rose disease on some level."

Still, they said, "the central conclusion from this comprehensive work is concerning and suggests that one of the most widely used drugs in patients may mitigate the benefit of cancer immunotherapy. While this study requires validation before we radically eliminate the use of APAP in our patients, the data require all of us who treat patients with immune checkpoint inhibitors to reexamine whether our patients on APAP really need to be."

Pain is the most common symptom of patients with advanced cancer, and APAP, alone or in combination, is a first-line option for pain control, Bessede and colleagues noted.

While generally considered safe to use in patients with cancer, some prior evidence has also suggested APAP may have negative immunomodulatory effects.

For example, preclinical studies showed that APAP can inhibit and . Clinical studies have produced evidence that APAP and/or neutralizing antibody response in patients with chickenpox or rhinovirus. Additionally, randomized studies showed in pediatric patients taking APAP for fever. The CDC use of APAP or other antipyretics before or at the time of vaccination.

Against that background evidence, the authors conducted a study to examine the effects of APAP on ICB efficacy in patients with advanced cancer. The investigation included three patient cohorts: the trial of nivolumab in advanced renal cell carcinoma and the French and studies of immunotherapy for advanced or metastatic solid tumors.

Key Findings

The results from CheckMate 025 showed that absence of APAP was associated with a 33% reduction in the mortality hazard among patients treated with nivolumab (95% CI 0.52-0.88, P=0.004).

Data from PREMIS showed that detectable ADAP was associated with a median PFS of 2.63 months versus 5.03 months for patients without ADAP (95% CI 0.53-0.91, P=0.009) and a median OS of 8.43 vs 14.93 months (95% CI 0.32-0.69, P<0.0001). On multivariate analysis, ADAP plasma levels maintained an independent association with PFS and OS.

The BIP analysis yielded response rates of 0% versus 29.4% for patients with and without detectable ADAP levels (P=0.015). Median PFS was more than twice as long in patients without detectable ADAP (4.72 vs 1.87 months, 95% CI 0.30-1.32, P=0.219), as was median OS (16.56 vs 7.87 months, 95% CI 0.3-1.63, P=0.412), although neither difference achieved statistical significance.

In the preclinical studies, ADAP levels did not affect survival, but substantially more animals without detectable ADAP were tumor free at the end of treatment.

Correction: A previous version of this article referred to "patients" in the last paragraph rather than "animals."

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