Missing content? – Request curation!
Request curation for specific Genes, Variants, or PubMed publications.
Have questions, comments, or suggestions? - Let us know!
Email us at : ckbsupport@genomenon.com
| Ref Type | Journal Article | ||||||||||||
| PMID | (35363510) | ||||||||||||
| Authors | Eckstein OS, Allen CE, Williams PM, Roy-Chowdhuri S, Patton DR, Coffey B, Reid JM, Piao J, Saguilig L, Alonzo TA, Berg SL, Ramirez NC, Jaju A, Mhlanga J, Fox E, Hawkins DS, Mooney MM, Takebe N, Tricoli JV, Janeway KA, Seibel NL, Parsons DW | ||||||||||||
| Title | 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. | ||||||||||||
|
|||||||||||||
| URL | |||||||||||||
| Abstract Text | 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.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.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.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. | ||||||||||||
| Molecular Profile | Treatment Approach |
|---|
| Gene Name | Source | Synonyms | Protein Domains | Gene Description | Gene Role |
|---|
| Therapy Name | Drugs | Efficacy Evidence | Clinical Trials |
|---|
| Drug Name | Trade Name | Synonyms | Drug Classes | Drug Description |
|---|
| Gene | Variant | Impact | Protein Effect | Variant Description | Associated with drug Resistance |
|---|
| Molecular Profile | Indication/Tumor Type | Response Type | Therapy Name | Approval Status | Evidence Type | Efficacy Evidence | References |
|---|---|---|---|---|---|---|---|
| HRAS act mut | Advanced Solid Tumor | no benefit | Selumetinib | Clinical Study - Cohort | Actionable | In a Phase II trial (Pediatric MATCH), Koselugo (selumetinib) treatment was tolerated but did not result in an objective response in pediatric patients with advanced solid tumors including high-grade glioma (n=8) and rhabdomyosarcoma (n=7) harboring MAPK pathway alterations including BRAF V600E (n=2), activating KRAS (n=8)/HRAS (n=1)/NRAS (n=3) or inactivating NF1 (n=7) mutations, with a 6-month progression-free survival of 15% (3/20) and 3 stable disease as best response (PMID: 35363510; NCT03213691). | 35363510 |
| NRAS act mut | Advanced Solid Tumor | no benefit | Selumetinib | Clinical Study - Cohort | Actionable | In a Phase II trial (Pediatric MATCH), Koselugo (selumetinib) treatment was tolerated but did not result in an objective response in pediatric patients with advanced solid tumors including high-grade glioma (n=8) and rhabdomyosarcoma (n=7) harboring MAPK pathway alterations including BRAF V600E (n=2), activating KRAS (n=8)/HRAS (n=1)/NRAS (n=3) or inactivating NF1 (n=7) mutations, with a 6-month progression-free survival of 15% (3/20) and 3 stable disease as best response (PMID: 35363510; NCT03213691). | 35363510 |
| BRAF V600E | Advanced Solid Tumor | no benefit | Selumetinib | Case Reports/Case Series | Actionable | In a Phase II trial (Pediatric MATCH), Koselugo (selumetinib) treatment was tolerated but did not result in an objective response in pediatric patients with advanced solid tumors including high-grade glioma (n=8) and rhabdomyosarcoma (n=7) harboring MAPK pathway alterations including BRAF V600E (n=2), activating KRAS (n=8)/HRAS (n=1)/NRAS (n=3) or inactivating NF1 (n=7) mutations, with a 6-month progression-free survival of 15% (3/20) and 3 stable disease as best response (PMID: 35363510; NCT03213691). | 35363510 |