Everolimus and de novo malignancies after liver transplantation: A nationwide emulated trial using real-world data

Liver transplantation (LT) is associated with an increased risk of de novo malignancies (DNMs). Everolimus is an mTOR inhibitor with immunosuppressive and potentially antineoplastic properties. We aimed to evaluate the association between everolimus use and the incidence of DNMs following LT.

Emulated target trials were conducted using French nationwide administrative health records. The cloning-censoring-weighting approach was applied to estimate the effects of everolimus initiation, everolimus discontinuation, and concomitant tacrolimus use among everolimus users. The primary outcome was the cumulative incidence of DNMs. Secondary outcomes included overall survival and site-specific cancer incidence.

A total of 7,981 patients underwent LT for cirrhosis or hepatocellular carcinoma (44%) between 2009 and 2020. The 10-year cumulative incidence of DNMs was 25.7%. DNMs were less frequent among patients who initiated everolimus within the first 3 years after LT (hazard ratio [HR] 0.84; 95% CI 0.79-0.88). Everolimus discontinuation was associated with an increased risk of DNMs (HR 1.34; 95% CI 1.21-1.45), whereas concomitant tacrolimus use was not significantly associated with DNM risk (HR 1.03; 95% CI 0.83-1.21). Site-specific emulated target trials demonstrated lower incidences of bladder, hematological, lung, prostate, skin, and lymphoid malignancies with everolimus use. The main findings remained robust in sensitivity analyses using alternative definitions of lag times and grace periods.

Sustained everolimus exposure was associated with a lower incidence of de novo malignancies after LT. These findings support everolimus-based immunosuppressive strategies incorporating calcineurin inhibitor minimization to potentially reduce long-term oncologic risk.

This study addressed the lack of randomized evidence regarding the role of everolimus (EVR) in preventing de novo malignancies after liver transplantation by leveraging a causal inference framework applied to nationwide data. These findings are important for transplant physicians, researchers, and policymakers, as they suggest that sustained EVR exposure is associated with a reduced risk of post-transplant malignancies without compromising overall survival. In practice, this supports the consideration of EVR as part of immunosuppressive strategies and highlights the potential risks associated with its discontinuation. These results may inform clinical decision-making and future research on optimizing long-term immunosuppression to balance graft protection and cancer risk.