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| Authors | Kieuhoa Tran Vo, Amit J. Sabnis, Paul M. Williams, Sinchita Roy-Chowdhuri, David R. Patton, Brent Coffey, Joel M. Reid, Jin Piao, Lauren Saguilig, Todd Allen Alonzo, Stacey L. Berg, Alok Jaju, Elizabeth Fox, Douglas S. Hawkins, Margaret M. Mooney, Naoko Takebe, James V. Tricoli, Katherine A. Janeway, Nita Seibel, Donald Williams Parsons | ||||||||||||
| Title | Ulixertinib in patients with tumors with MAPK pathway alterations: Results from NCI-COG Pediatric MATCH trial Arm J (APEC1621J). | ||||||||||||
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| URL | https://ascopubs.org/doi/10.1200/JCO.2022.40.16_suppl.3009 | ||||||||||||
| Abstract Text | 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. | ||||||||||||
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| Gene Name | Source | Synonyms | Protein Domains | Gene Description | Gene Role |
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| Therapy Name | Drugs | Efficacy Evidence | Clinical Trials |
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| Gene | Variant | Impact | Protein Effect | Variant Description | Associated with drug Resistance |
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| Molecular Profile | Indication/Tumor Type | Response Type | Therapy Name | Approval Status | Evidence Type | Efficacy Evidence | References |
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| BRAF V600E | central nervous system cancer | predicted - sensitive | Ulixertinib | Case Reports/Case Series | Actionable | In a Phase II trial (APEC1621J), Ulixertinib (BVD-523) treatment resulted in a 6-month progression-free survival rate of 37% but no objective response in pediatric and young adult patients with advanced solid tumors harboring MAPK pathway activation, however, a patient with glioneuronal tumor harboring a BRAF V600E achieved prolonged stable disease and remained on treatment for 9 cycles (J Clin Oncol 40, no. 16_suppl (June 01, 2022) 3009; NCT03698994). | detail... |
| BRAF fusion | low grade glioma | predicted - sensitive | Ulixertinib | Case Reports/Case Series | Actionable | In a Phase II trial (APEC1621J), Ulixertinib (BVD-523) treatment resulted in a 6-month progression-free survival rate of 37% but no objective response in pediatric and young adult patients with advanced solid tumors harboring MAPK pathway activation, however, a patient with low grade glioma harboring a BRAF fusion achieved prolonged stable disease and remained on treatment for 7 cycles (J Clin Oncol 40, no. 16_suppl (June 01, 2022) 3009; NCT03698994). | detail... |
| BRAF fusion | high grade glioma | predicted - sensitive | Ulixertinib | Case Reports/Case Series | Actionable | In a Phase II trial (APEC1621J), Ulixertinib (BVD-523) treatment resulted in a 6-month progression-free survival rate of 37% but no objective response in pediatric and young adult patients with advanced solid tumors harboring MAPK pathway activation, however, a patient with high grade glioma harboring a BRAF fusion achieved prolonged stable disease and remained on treatment for 15 cycles (J Clin Oncol 40, no. 16_suppl (June 01, 2022) 3009; NCT03698994). | detail... |