Phase II Study of Selumetinib in Children and Young Adults With Tumors Harboring Activating Mitogen-Activated Protein Kinase Pathway Genetic Alterations: Arm E of the NCI-COG Pediatric MATCH Trial

Abstract

Purpose: The NCI-COG Pediatric MATCH trial assigns patients age 1-21 years with relapsed or refractory solid tumors, lymphomas, and histiocytic disorders to phase II studies of molecularly targeted therapies on the basis of detection of predefined genetic alterations. Patients with tumors harboring mutations or fusions driving activation of the mitogen-activated protein kinase (MAPK) pathway were treated with the MEK inhibitor selumetinib.

Methods: Patients received selumetinib twice daily for 28-day cycles until disease progression or intolerable toxicity. The primary end point was objective response rate; secondary end points included progression-free survival and tolerability of selumetinib.

Results: Twenty patients (median age: 14 years) were treated. All were evaluable for response and toxicities. The most frequent diagnoses were high-grade glioma (HGG; n = 7) and rhabdomyosarcoma (n = 7). Twenty-one actionable mutations were detected: hotspot mutations in KRAS (n = 8), NRAS (n = 3), and HRAS (n = 1), inactivating mutations in NF1 (n = 7), and BRAF V600E (n = 2). No objective responses were observed. Three patients had a best response of stable disease including two patients with HGG (NF1 mutation, six cycles; KRAS mutation, 12 cycles). Six-month progression-free survival was 15% (95% CI, 4 to 34). Five patients (25%) experienced a grade 3 or higher adverse event that was possibly or probably attributable to study drug.

Conclusion: A national histology-agnostic molecular screening strategy was effective at identifying children and young adults eligible for treatment with selumetinib in the first Pediatric MATCH treatment arm to be completed. MEK inhibitors have demonstrated promising responses in some pediatric tumors (eg, low-grade glioma and plexiform neurofibroma). However, selumetinib in this cohort with treatment-refractory tumors harboring MAPK alterations demonstrated limited efficacy, indicating that pathway mutation status alone is insufficient to predict response to selumetinib monotherapy for pediatric cancers.

Trial registration: ClinicalTrials.gov NCT03213691.

FIG 1.

Patient flow diagram of NCI-COG Pediatric MATCH arm E. Other reasons for ineligibility were inadequate cardiac function (n = 2) and known ophthalmologic condition (n = 1). LGG, low-grade glioma.

FIG 2.

Diagnoses and actionable MAPK pathway mutations of arm E patients. (A) Pie chart of the histologic diagnoses of the 58 matched patients. (B) Pie chart of the histologic diagnoses of the 20 treated patients. (C) Pie chart of the types of actionable MAPK pathway tumor alterations detected in the 58 matched patients (n = 60 mutations). (D) Pie chart of the types of actionable MAPK pathway tumor alterations detected in the 20 treated patients (n = 21 mutations). (E) Tumor variants detected by gene and patient. The genes with variants are indicated for each patient (each column represents a patient). The 20 patients treated in arm E are on the left side of the figure; the remainder of the matched patients are on the right. The histogram on the left gives the number of variants detected for each alteration type. Actionable MAPK pathway alterations are in the top rows of the figure (KRAS mutation to BRAF other); other cancer gene alterations identified by the tumor panel testing are listed in the rows below. HGG, high-grade glioma; LGG, low-grade glioma; MAPK, mitogen-activated protein kinase; Mut, mutation; RMS, rhabdomyosarcoma.

FIG 3.

(A) Swimmer plot and (B) Kaplan-Meier curve of the 20 treated arm E patients. HGG, high-grade glioma; LGG, low-grade glioma; PFS, progression-free survival; RMS, rhabdomyosarcoma.

FIG A1.

Projected and observed accrual to arm E. Arm E was activated in July 2017 with the first patient enrolling in December 2017. The trial was temporarily closed after the 20th patient was enrolled in August 2019 and permanently closed in September 2020.