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

BACKGROUND AND AIMS: 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.

METHODS

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.

RESULTS

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.

CONCLUSIONS

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.