Background

People with Neurofibromatosis type 1 (NF1) are at risk of developing benign and malignant peripheral nerve sheath tumors (MPNST). In NF1, the overall lifetime risk of MPNST is estimated at 8%-13%, with increased risk associated with specific germline mutations and larger benign tumor burden. Selumetinib, a mitogen-activating protein kinase kinase inhibitor (MEKi), was the first FDA-approved therapy for children with inoperable, symptomatic benign nerve sheath tumors known as plexiform neurofibromas (PN). While clinical and preclinical studies indicate that MEKi monotherapy is unlikely an effective treatment for MPNST, the potential impact of long-term MEKi therapy on the risk of malignant transformation of benign PN is not yet known.

Methods

We evaluated the impact of selumetinib on the development of MPNST in a pre-clinical orthotopic mouse model of Nf1-Arf mutant Schwann cells. In addition, we analyzed MPNST development on our phase 1/2 clinical trial of selumetinib for PN (NCT01362803).

Results

In the preclinical mouse model, selumetinib did not accelerate the development or growth of MPNST. On the selumetinib clinical trial, 4 of 99 participants developed an MPNST either during or shortly after treatment. All were at increased risk for developing MPNST based on a large PN tumor burden, NF1 microdeletion, or presence of a pre-malignant atypical neurofibroma prior to starting selumetinib treatment.

Conclusions

While these findings do not indicate acceleration of MPNST development on selumetinib, patients receiving MEKi for PN, in particular those with high-risk features, remain at risk for malignant transformation and should be monitored accordingly.

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