MEK inhibition achieves robust and durable responses in Erdheim-Chester disease

Erdheim-Chester disease (ECD) is a rare histiocytic neoplasm characterized by heterogeneous clinical manifestations and limited evidence to guide targeted therapy. While MEK inhibitors (MEKi) are increasingly used, data on their real-world efficacy, durability, and safety remain incomplete. We analyzed outcomes of patients with ECD treated with MEKi monotherapy across eight countries and assessed the dynamics and predictors of response, treatment retention, and the safety profile of MEKi. We included 170 patients and were able to evaluate response in 159 (94%) of them. Objective responses were observed in 112 patients (70%), disease stabilization in 35 (22%), and disease progression in 12 (8%). Response rates were independent of treatment lines and underlying molecular alterations. The median time to best response was 14 months, with an estimated 2-year probability of response of 61% (95% CI 51%-67%). In multivariable analysis, dyslipidemia (odds ratio [OR] 0.359, 95% CI 0.171-0.745) and neurodegeneration (OR 0.354, 95% CI 0.144-0.864) were associated with a lower probability of response to MEKi, while cutaneous and gastrointestinal involvement with a higher probability. After a median follow-up of 27 months (interquartile range [IQR] 12-57), the treatment retention rate was 76%, with most discontinuations attributable to toxicity. Adverse events were reported in 106 patients (62%) and were severe in 39 patients (23%). The estimated 2-year event-free survival was 65% (95% CI 57%-72%), and the estimated 2-year overall survival was 80% (95% CI 72%-86%). MEKi monotherapy provides robust and durable clinical efficacy in patients with ECD, with high response rates and favorable long-term outcomes, despite a substantial burden of toxicity.