Ulixertinib in patients with tumors with MAPK pathway alterations: Results from NCI-COG Pediatric MATCH trial Arm J (APEC1621J).

3009 Background: The NCI-Children’s Oncology Group (COG) Pediatric Molecular Analysis for Therapy Choice (MATCH) trial assigns patients age 1 to 21 years with relapsed or refractory solid tumors, lymphomas, and histiocytic disorders to phase 2 treatment arms of molecularly-targeted therapies based on genetic alterations detected in their tumor. Arm J evaluated the ERK1/2 inhibitor ulixertinib (BVD-523FB) in patients whose tumors harbored activating alterations in the MAPK pathway ( ARAF, BRAF, HRAS, KRAS, NRAS, MAPK1, MAP2K1, GNA11, GNAQ hotspot mutations; NF1inactivating mutations; BRAF fusions). Methods: As there were no prior pediatric data, ulixertinib was initially tested in a dose escalation cohort using a rolling 6 design to establish the recommended phase 2 dose (RP2D) before proceeding with enrollment to the phase 2 cohort. Ulixertinib was administered at 260 mg/m2/dose PO BID (dose level 1, DL1, n = 15) or 350 mg/m2/dose PO BID (dose level 2, DL2, n = 5). Patients were treated on continuous 28-day cycles for up to 2 years, until disease progression or intolerable toxicity; response assessment occurred every 2-3 cycles. The primary endpoint was objective response rate; secondary endpoints included safety/tolerability and progression-free survival (PFS). Results: Twenty patients (median age 12 years; range 5-20) were enrolled between November 2018 and March 2021. All patients were evaluable for response. High-grade glioma (HGG, n = 7) was most common, with CNS tumors comprising 55% (11/20) of diagnoses; all CNS tumors except one (HGG with KRAS and NF1 mutations) harbored BRAF fusions or V600 mutations. Rhabdomyosarcoma (n = 5) was the most frequent non-CNS diagnosis, with NRAS mutations detected in 4 tumors. DL1 was declared the RP2D after first-cycle dose limiting toxicities (DLTs) occurred in 1/6 DLT-evaluable patients at DL1 and 2/5 patients at DL2 in the dose escalation cohort. Any-cycle DLTs in 8 patients in the dose escalation and primary cohorts included fatigue, anorexia, rash, nausea, vomiting, diarrhea, dehydration, increased creatinine, hypoalbuminemia, hypernatremia, and hip fracture. No objective responses were observed. Six-month PFS was 37% (95% CI: 17%, 58%). Three patients with CNS tumors achieved stable disease > 6 months (HGG with BRAF fusion, 15 cycles; glioneuronal tumor with BRAF V600E, 9 cycles; low-grade glioma with BRAF fusion, 7 cycles). Analyses of correlative studies, including pharmacokinetics and circulating tumor DNA, are ongoing. Conclusions: The pediatric RP2D of ulixertinib was established as 260 mg/m2/dose PO BID. There were no objective responses in this cohort of children and young adults with treatment-refractory tumors with activating MAPK alterations. Clinical benefit of prolonged disease control was observed in 3 patients with BRAF-altered gliomas and glioneuronal tumors. Clinical trial information: NCT03698994.