Identification of targetable molecular alterations in the NCI-COG Pediatric MATCH trial.

Abstract

10011 Background: The screening protocol for the NCI-Children’s Oncology Group (COG) Pediatric Molecular Analysis for Therapy Choice (MATCH) trial detects tumor alterations that are used to assign patients with treatment-refractory or recurrent cancers to phase 2 treatment arms of molecularly-targeted therapies. Methods: Patients age 1 to 21 years old with treatment-refractory or recurrent solid tumors, non-Hodgkin lymphomas, or histiocytic disorders treated at U.S. based COG sites are eligible. DNA and RNA extracted from FFPE tumor samples are sequenced using an Oncomine cancer gene panel for detection of mutations, amplifications, and fusions. Loss of SMARCB1, SMARCA4, and PTEN expression is detected by immunohistochemistry. Lists of actionable mutations (aMOIs) based upon available clinical and pre-clinical data are used a priori to determine eligibility for treatment arms. Results: Between 7/24/17 and 12/31/18, 422 patients with a median age of 13 years (range 1-21) were enrolled from 93 COG sites. Solid tumors comprised 71% (n = 300) of diagnoses, CNS tumors 24% (n = 101) and lymphomas/histiocytoses 5% (n = 21). A tumor sample was submitted for 390 patients, sequencing was attempted for 370 (95%), and results were confirmed for 357 (92%). Median turn-around time was 15 days. An aMOI for at least one of the 10 current treatment arms was identified in 112 patients (29%, 95% CI 24%-33%); 95 patients (24%, 95% CI 20%-29%) were assigned to a treatment arm with 39 patients (10%, 95% CI 7%-13%) enrolled to date. The aMOI rate was similar in patients less than 12 years of age (35%) compared to patients 12 years and older (25%). Actionable MAPK pathway alterations were found in 11% of patients (n = 41), most often HRAS/ KRAS/ NRAS mutations (n = 16), BRAF mutations or fusions (n = 14), or NF1 mutations (n = 11). Other genes with recurrent aMOIs included SMARCB1 (n = 14), ALK (n = 8), CDK4 (n = 8), PIK3CA (n = 7), PTEN (n = 7), FGFR1 (n = 5), and BRCA1/BRCA2 (n = 5). Conclusions: Approximately one-quarter of patients with tumor submitted for Pediatric MATCH screening have been assigned to an investigational therapy, facilitating the evaluation of molecularly-targeted agents in biomarker-positive pediatric cohorts through a collaborative nationwide study. Clinical trial information: NCT03155620.