Actionable Tumor Alterations and Treatment Protocol Enrollment of Pediatric and Young Adult Patients With Refractory Cancers in the National Cancer Institute-Children's Oncology Group Pediatric MATCH Trial

Abstract

Purpose: The National Cancer Institute-Children's Oncology Group Pediatric MATCH trial aimed to facilitate evaluation of molecular-targeted therapies in biomarker-selected cohorts of childhood and young adult patients with cancer by screening tumors for actionable alterations.

Patients and methods: Tumors from patients age 1-21 years with refractory solid tumors, lymphomas, or histiocytic disorders were subjected to cancer gene panel sequencing and limited immunohistochemistry to identify actionable alterations for assignment to phase II treatment arms. The rates of treatment arm assignment and enrollment were compared between clinical and demographic groups.

Results: Testing was completed for 94.7% of tumors submitted. Actionable alterations were detected in 31.5% of the first 1,000 tumors screened, with treatment arm assignment and enrollment occurring in 28.4% and 13.1% of patients, respectively. Assignment rates varied by tumor histology and were higher for patients with CNS tumors or enrolled at Pediatric Early Phase Clinical Trials Network sites. A reported history of prior clinical molecular testing was associated with higher assignment and enrollment rates. Actionable alterations in the mitogen-activated protein kinase signaling pathway were most frequent (11.2%). The most common reasons provided for not enrolling on treatment arms were patients receiving other treatment or poor clinical status.

Conclusion: The Pediatric MATCH trial has proven the feasibility of a nationwide screening Protocol for identification of actionable genetic alterations and assignment of pediatric and young adult patients with refractory cancers to trials of molecularly targeted therapies. These data support the early use of tumor molecular screening for childhood patients with cancer whose tumors have not responded to standard treatments.

Trial registration: ClinicalTrials.gov NCT03155620.

FIG 1.

Pediatric MATCH trial arms and actionable cancer genes. The screening protocol and the seven treatment arms (A, C, D, E, F, G, and H) were activated in July 2017. Six additional treatment arms (B, I, J, K, M, and N) had been activated by the time the 1,000th patient screened was enrolled in October 2020. Arms C and E were closed after completion of study accrual.

FIG 2.

Patient flow diagram for Pediatric MATCH trial. Reasons provided for matched patients not enrolling in treatment protocols are described further in the Data Supplement.

FIG 3.

Genomic landscape of tumors with actionable alterations in the Pediatric MATCH trial (n = 315). A genomic waterfall plot (A) displaying the genes with most frequent actionable alterations at the top of the figure, categorized by variant type (mutation, loss/mutation, fusion, and amplification). Each tumor is represented by a column. The variant types for the less common actionable genes (shaded in purple) are not specified. Concurrent alterations in nonactionable genes occurring at a frequency of 1% or greater in the full study cohort are presented at the bottom of the figure. The lower bar categorizes the tumors on the basis of Dx. For the purposes of this figure, negative expression of SMARCB1, SMARCA4, or PTEN by IHC is assigned the loss/mutation variant type. (B) Twenty genes with tumor alterations detected in at least 1% of Pediatric MATCH patients screened. Actionable genes for Pediatric MATCH study arms are marked in blue. Genes with nonactionable alterations detected in patient tumors are marked in red. aMOI, actionable mutation; AT/RT, tumor histology of atypical teratoid rhaboid tumor; Dx, diagnosis; IHC, immunohistochemistry.

FIG 4.

Actionable MAPK pathway alterations by tumor type. A total of 115 alterations were detected in 112 tumors. (A) Tumor diagnoses with actionable MAPK pathway alterations identified. (B-G) Specific MAPK alterations detected in selected diagnostic groups and tumor types. The number of alterations in each group is shown. (B) All tumors, (C) non-CNS solid tumors, (D) CNS solid tumors, (E) RMS, (F) LGG, and (G) HGG. HGG, high-grade glioma; LGG, low-glade glioma; MAPK, mitogen-activated protein kinase; MPNST, malignant peripheral nerve sheath tumor; RMS, rhabdomyosarcoma.

FIG A1.

Geographic distribution of COG sites at which Pediatric MATCH patients were enrolled. COG, Children's Oncology Group.

FIG A2.

Projected and actual Pediatric MATCH screening protocol accrual.

FIG A3.

Actionable alteration rates for Pediatric MATCH study arms by tumor type. Study arms: A (larotrectinib), B (erdafitinib), C (tazemetostat), and D (samotolisib); MAPK arms (E, selumetinib; G, vemurafenib; J, ulixertinib; and M, tipifarnib), F (ensartinib), H (olaparib), K (ivosidenib), and N (selpercatinib). (A) All tumors, (B) non-CNS solid tumors, (C) CNS solid tumors, (D) osteosarcoma, (E) rhabdomyosarcoma, (F) Ewing sarcoma, (G) high-grade glioma, (H) neuroblastoma, and (I) low-grade glioma. MAPK, mitogen-activated protein kinase.