Abstract
The event-free survival of pediatric low-grade gliomas is poor, and
patients often require multiple treatment strategies. While MEK and RAF
inhibitors are efficacious in early-phase trials, not all patients
respond and many experience progression following completion of therapy.
Evaluating combination therapies that may enhance efficacy or prolong
disease stabilization is warranted. We report our institutional
experience using concurrent trametinib and lenalidomide in the treatment
of primary pediatric central and peripheral nervous system tumors. Two
of four patients using this combination therapy experienced severe
thromboembolic events necessitating discontinuation of therapy. This
combination requires further investigation, and we urge caution if used.
Introduction Pediatric low-grade gliomas (pLGGs) are the most common central nervous
system (CNS) tumors in childhood.1 Outcomes for pLGGs
are generally excellent, with a 20-year overall survival (OS) between
85-96%.2-4 However, event-free survival (EFS) is
poor, with data from Children’s Oncology Group A9952 demonstrating an
EFS of 45% for all patients.5 Patients consequently
often require multiple treatment strategies.
Complete surgical resection is the mainstay of treatment, however, often
is not feasible due to tumor location. Carboplatin-containing
chemotherapy regimens are the standard upfront therapy for pLGGs, but
there is no consensus on treatment following
recurrence.5-10
The hallmark of pLGGs are genetic aberrations of the mitogen-activated
protein kinase (MAPK) pathway, which lead to constitutive pathway
activation.11-14 MEK and RAF inhibitors target this
pathway and are well tolerated and efficacious in reducing tumor size
and improving EFS in phase 1 and 2 trials in patients with recurrent
pLGGs.15-19 However, not all patients respond to
monotherapy, and many experience progression after completion of
therapy. Thus, evaluating combination therapies that may enhance
efficacy or prolong disease stabilization is warranted.
Lenalidomide is an immunomodulatory agent with CNS penetration that
functions through anti-angiogenic, anti-inflammatory, and pro-apoptotic
effects, making it a promising candidate for the treatment of pediatric
CNS tumors. Lenalidomide is well-tolerated in ongoing phase I trials for
recurrent pediatric malignancies, with an anti-tumor effect demonstrated
in recurrent pediatric CNS tumors.20-22 Given their
distinct mechanisms of action, concurrent MEK inhibitors and
lenalidomide may present a rational combinatorial therapy. Further, both
have available safety and dosing data in pediatric patients. Here we
describe our institutional experience treating pediatric patients with a
MEK inhibitor and lenalidomide concurrently, which to our knowledge has
not been described.