Could intermediate use of H1-antihistamines alongside ICIs extend OS in lung cancer?

A retrospective territory-wide cohort study by the Chinese University of Hong Kong (CUHK) reports an association between intermediate use of H₁-antihistamines and longer overall survival (OS) in patients with lung cancer treated with immune checkpoint inhibitors (ICIs).

Recent translational research suggests an upregulation of histamine and histamine receptor H₁ (HRH₁) expression in the immunosuppressive tumour microenvironment, while also demonstrating that HRH₁ blockade reverses T-cell dysfunction. Retrospective evaluation of concomitant use of H₁‐antihistamines during ICI treatment in a US study found statistically significant improvements in OS for lung and skin malignancies and reported similar trends in breast and colon malignancies. [Cancer Cell 2022;40:36-52.e9]

Using data from the Clinical Data Analysis and Reporting System (CDARS), the researchers identified 1,740 adult cancer patients (mean age, 61.9 years; male, 65.1 percent) who received at least one dose of ICI between 1 July 2014 and 31 December 2019 and were alive 1 month later. Primary lung (30.4 percent) and liver (17.6 percent) malignancies were the most common, while the most commonly prescribed ICIs were pembrolizumab (51.1 percent), nivolumab (34.3 percent), and atezolizumab (14.4 percent). [Cancer Med 2025;14:e70583]

During the exposure period defined as 1 month before and 1 month after the first ICI dose, 83.6 percent of patients were prescribed H₁-antihistamines. The most commonly prescribed agents were chlorpheniramine (79.9 percent), loratadine (22.2 percent) and hydroxyzine (13.2 percent). Patients could switch to a different generation of H₁‐antihistamines more than once during the exposure period.

Patients prescribed H₁-antihistamines were categorized by quartiles of percentages of days’ supply during the exposure period into: 1) minimal users (0–25 percent); 2) infrequent users (25–50 percent); 3) intermediate users (50–75 percent); and 4) frequent users (75–100 percent).

For patients with primary lung malignancies, intermediate use of H₁-antihistamines served as an independent protective factor against mortality (adjusted hazard ratio [aHR], 0.223; 95 percent confidence interval [CI], 0.052–0.958; p=0.044). The opposite was true for intermediate H₁-antihistamines users with primary liver malignancies, who were 2.6 times more likely to die of any cause within 6 months after receiving the first dose of ICI (aHR, 2.585; 95 percent CI, 1.227–5.446; p=0.013). Frequent H₁-antihistamine use was found to be independently associated with a 72 percent increase in mortality risk in patients with primary lung malignancies (aHR 1.723; 95 percent CI, 1.024–2.901; p=0.040). No significant correlation was found between H₁-antihistamine use and mortality among patients with other primary malignancies or missing diagnosis codes.

The researchers hypothesized that intermediate use of H₁-antihistamines may extend OS in lung cancer because lung malignancies are typically more aggressive and exhibit a greater propensity for metastasis to various organs than liver cancer, while preclinical data indicate that HRH₁ blockade enhances the antimetastatic immune response. Additionally, clinical retrospective data support the observation that patients with metastatic cancer who received ICIs in conjunction with antihistamines experienced independently improved survival outcomes. [Anticancer Drugs 2024;35:190-194] On the other hand, the superimposed chronic T-cell–mediated allergic inflammation, indicative of redirection of T-cells toward a pathogenic and proinflammatory phenotype during ICI treatment, might explain the significantly increased mortality risk despite H₁‐antihistamine use in frequent users. [J Allergy Clin Immunol 2016;138:639-652]