Cardiotoxicity of trametinib monotherapy in adults with neurofibromatosis type 1: Results from the TRAIN study

MEK1/2 inhibitors are increasingly used in neurofibromatosis type 1 (NF1) and can cause cancer therapy–related cardiac dysfunction (CTRCD). Cardiotoxicity rates of up to 12% have been reported in combination therapy, and up to 7% in monotherapy trials. Cardiac monitoring is recommended, but data on trametinib in NF1 remain limited. Therefore, we evaluated the incidence, timing, and clinical characteristics of CTRCD in adults with NF1 receiving trametinib monotherapy. The phase II single-arm TRAIN trial included NF1 patients receiving trametinib 2 mg daily. Serial cardiovascular assessments and N-terminal pro–B-type Natriuretic Peptide (NT-proBNP) measurements were collected over 2 years. CTRCD was defined as mild, moderate or severe per 2022 European Society for Cardiology cardio-oncology guidelines. Of 30 patients, 7 (23%) developed CTRCD: 1 severe, 4 moderate and 2 mild. Median onset time was 5 months (range 1–12 months). All cases were asymptomatic and reversible. One severe case required permanent discontinuation, after which LVEF recovered. NT-proBNP remained normal in 6 cases; only the severe case showed a marked rise. No baseline clinical or cardiovascular parameters could predict CTRCD. In this NF1 cohort, cardiotoxicity occurred in 23% of patients but only one case required trametinib discontinuation. Events occurred within the first year, were usually moderate, and reversible. NT-proBNP remained normal in most cases but may help identify patients needing echocardiography. We recommend continuing echocardiography during the first year, with consideration for less frequent monitoring thereafter based on clinical findings. However, further data are needed for long-term surveillance. Overview of cardiotoxicity monitoring and findings in NF1 patients treated with trametinib. Thirty patients received 2 mg of trametinib daily and underwent serial NT-proBNP and echocardiographic monitoring. CTRCD occurred in 23% (n = 7), typically within the first year. Two cases were mild and four cases were moderate and reversible, one patient had severe CTRCD. Left graph shows median LVEF trends in patients with and without CTRCD. Right graph illustrates NT-proBNP elevation and concurrent GLS/LVEF decline in the severe case. Findings support echocardiography for only the first year of treatment. • Trametinib monotherapy caused heart dysfunction in 23% of patients. • Most cardiotoxicity cases were mild, asymptomatic, and fully reversible. • NT-proBNP levels remained normal in 6 of 7 patients with cardiac dysfunction. • No new cardiac dysfunction occurred after the first year of treatment.