Concomitant antihistamine administration is associated with improved survival outcomes in patients with locally advanced or metastatic urothelial carcinoma treated with atezolizumab. Analysis of individual participant data from IMvigor210 and IMvigor211

Objectives: Survival outcomes of patients with metastatic urothelial carcinoma (mUC) are still suboptimal and strategies to enhance response to immune-oncology (IO) compounds are under scrutiny. In preclinical studies, it has been demonstrated that antihistamines may reverse macrophage immunosuppression, reactivate T cell cytotoxicity, and enhance the immunotherapy response. We aimed to evaluate the role of concomitant antihistamines administration on oncological outcomes among patients with mUC. Materials and Methods: We relied on individual patient data from IMvigor210 (phase II single-arm trial on second line atezolizumab for mUC) and IMvigor211 trials (phase III randomized trial on second line atezolizumab vs chemotherapy for mUC). Among individuals treated with IO we identified patients who did and did not receive antihistamines. Multivariable Cox or competing-risks regression models were used to predict progression-free survival (PFS), overall survival (OS), and cancer-specific survival (CSS). The impact of antihistamines on the outcomes was assessed after adjusting for potential confounders. Results: Among 896 patients with locally advanced or metastatic urothelial cancer who had progressed after first-line chemotherapy, 155 (17 %) received antihistamines during the delivery of IO. Patients receiving antihistamines had longer OS (Hazard Ratio [HR]:0.59; 95 % Confidence interval [CI]: 0.47-0.74; P < 0.001), PFS (HR:0.70; 95 %CI: 0.57-0.87; P = 0.001) and CSS [sHR:0.58; 95 %CI:0.45-0.75; P < 0.001)] relative to those who had not used antihistamine drugs. A sensitivity analysis, after the exclusion of patients who experienced adverse events and received antihistamines, yielded similar findings of prolonged CSS (sHR 0.78; 95 %CI: 0.59-0.98, P = 0.031) and OS (HR 0.71; 95 %CI: 0.52-0.94, P = 0.021). Conclusions: Concomitant antihistamines administration was associated with improved OS, CSS, and PFS in patients receiving atezolizumab as second line treatment for mUC. Further mechanistic and clinical investigation is warranted to elucidate the role of antihistamines in IO.