No detrimental association between antibiotic use and immune checkpoint inhibitor therapy: an observational cohort study comparing patients with ICI-treated and TKI-treated melanoma and NSCLC.

BACKGROUND: The role of antibiotics in malignancies treated with immune checkpoint inhibitors (ICI) remains unclear. Several studies suggested a detrimental impact of antibiotic use on the response to ICI, but were susceptible to confounding by indication. Our objective was therefore to assess whether the relationship between antibiotic use and ICI response is causative or merely associative. METHODS: A large, single-center observational cohort study was performed with individuals treated for either non-small cell lung carcinoma (NSCLC) or metastatic melanoma. An effect modification approach was used, aiming to estimate the association between antibiotic use and overall survival (OS) and compare these estimates between individuals receiving first-line ICI treatment versus those receiving first-line tyrosine kinase inhibitors (TKIs). Exposure of interest was antibiotic use within 30 days before the start of anticancer treatment. HRs for OS were estimated for antibiotics versus no antibiotics in each cohort using multivariable propensity adjusted analysis. The "true antibiotic effect" within the ICI versus TKI cohort was modeled using an interaction term. RESULTS: A total of 4534 patients were included, of which 1908 in the ICI cohort and 817 in the TKI cohort. Approximately 10% of patients in each cohort used antibiotics within 30 days before the start of anticancer treatment. Our results demonstrate a lack of synergistic interaction between current antibiotic use and ICI therapy in relation to OS: although antibiotic use was significantly associated with OS decline in the ICI cohort (HR=1.26 (95% CI 1.04 to 1.51)), a similar magnitude in OS decline was found within the TKI cohort (HR=1.24 (95% CI 0.95 to 1.62)). This was reflected by the synergy index (HR=0.96 (95% CI 0.70 to 1.31)), which implied no synergistic interaction between current antibiotic use and ICI. CONCLUSION: This study strongly suggests that there is no causal detrimental association between antibiotic use and ICI therapy outcome when looking at OS in individuals with malignant melanoma or NSCLC. The frequently observed inverse association between antibiotics and ICI response in previous studies is most likely driven by confounding by indication, which was confirmed by the findings in our reference TKI cohort.

Concomitant use of analgesics and immune checkpoint inhibitors in non-small cell lung cancer: A pharmacodynamics perspective.

The invention of immunotherapy, such as immune checkpoint inhibitors (ICIs) for advanced-stage non-small cell lung cancer (NSCLC), has become a new standard of care for a defined group of NSCLC patients. However, the possible impacts of ICI interactions with analgesics for alleviating cancer-related pain are unclear and lack clinical evidence. Many studies have indicated that opioids detrimentally affect the immune system, possibly harming patients of ongoing immunotherapy. Opioids may repress the immune system in various ways, including impairing T cell function, upregulating immunosuppressor Treg cells, and interrupting intestinal microflora composition that disrupts the entire immune system. Furthermore, opioids can influence tumor progression and metastasis directly as opioid receptors are overexpressed in several types of NSCLC. In contrast, another analgesic acting on cyclooxygenase (COX) inhibition (i.e., NSAIDs) may be a candidate for adjuvant therapy since COX-2 is also expressed in the tumor cells of NSCLC patients. In addition, COX-2 is associated with tumor proliferation and metastasis. Therefore, both prospective and retrospective studies should confirm the advantages and disadvantages of the concurrent use of analgesics and ICIs in a clinical setting.