Selumetinib in Children and Young Adults With Tumors That Have Activating MAPK Pathway Alterations

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In a phase II trial (arm E of the NCI-COG Pediatric MATCH trial) reported in the Journal of Clinical Oncology, Eckstein et al found that the MEK inhibitor selumetinib showed little activity in pediatric and young adult patients with tumors harboring activating MAPK pathway mutations or fusions.

As stated by the investigators, “The NCI-COG Pediatric MATCH trial assigns patients age[d] 1 to 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. [In the current trial], patients with tumors harboring mutations or fusions driving activation of the … MAPK pathway were treated with the MEK inhibitor selumetinib.”

Study Details

In the study, 20 patients (median age = 14 years) enrolled between December 2017 and August 2019 received selumetinib twice daily for 28-day cycles until disease progression or intolerable toxicity. The most common diagnoses were high-grade glioma (n = 7) and rhabdomyosarcoma (n = 7). Overall, 21 actionable mutations were identified, consisting of hotspot mutations in KRAS (n = 8), NRAS (n = 3), and HRAS (n = 1); inactivating mutations in NF1 (n = 7); and BRAF V600E (n = 2). The primary endpoint was objective response rate.

Key Findings

No objective responses were observed. Three patients had a best overall response of stable disease. One patient with high-grade glioma and a KRAS mutation had stable disease for 12 cycles before having disease progression on therapy. Another patient with high-grade glioma and NF1 and PTEN mutations had stable disease for six cycles before experiencing disease progression on therapy. One patient with plexiform neurofibroma and NF1 and BRCA2 mutations had stable disease for 13 cycles until treatment was stopped due to dose-limiting toxicity (uveitis).

Six-month progression-free survival was 15% (95% confidence interval = 4%–34%).

Grade ≥ 3 adverse events considered at least possibly related to treatment occurred in five patients (25%), including increased creatine phosphokinase, decreased lymphocyte count, and uveitis in one patient each and thromboembolic events in two, with one event resulting in death.

The investigators concluded, “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.”

Carl E. Allen, MD, PhD, of Texas Children’s Cancer and Hematology Centers, Baylor College of Medicine, is the corresponding author for the Journal of Clinical Oncology article.

Disclosure: The study was supported by the National Cancer Institute and St. Baldrick’s Foundation. For full disclosures of the study authors, visit

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