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.