NGS Is Effective in Identifying Actionable Genetic Alterations for Investigational Targeted Therapies in Paediatric and Young Adult Patients with Refractory Cancers

The National Cancer Institute (NCI)–Children’s Oncology Group (COG) Pediatric MATCH study demonstrated the feasibility of a nationwide screening and centralised testing Protocol to select patients with tumours harbouring actionable alterations for enrolment in clinical studies of molecularly targeted therapies. Study accrual exceeded projections, and tumour profiling was completed for the majority of patients, using predominantly archived FFPE samples. The screening Protocol has successfully matched patients to investigational therapies, with 28% of patients assigned to treatment arms and 13% enroled in those studies. Dr. D. Williams Parsons of the Texas Children’s Cancer and Hematology Center, Baylor College of Medicine in Houston, TX, US and colleagues, who published the findings on 30 March 2022 in the Journal of Clinical Oncology, commented that the study has provided access to clinical molecular screening and early-phase studies of molecularly targeted therapies for paediatric and young adult patients with cancer across the United States.

The authors wrote in the background that although outcomes for this population have improved, effective treatment options for most recurrent cancers are limited and novel approaches are needed. Significant research effort has focused on interrogation of the genomic landscapes of paediatric cancers, providing insight into tumour biology and revealing potentially targetable genetic alterations in key signalling pathways.

These alterations occur in a fraction of paediatric tumours, however, and often in multiple disease histologies, complicating evaluation of novel molecularly targeted agents. Access to investigational molecularly targeted therapies in children has also presented a limitation to the performance of biomarker-selected studies. Data are limited regarding the frequency of actionable tumour alterations in recurrent paediatric cancers, and the utility of a molecular screening approach for paediatric patients is not known. This study was developed to provide a national framework for investigational molecularly targeted therapies in biomarker-selected populations.

Centralised tumour sequencing was performed, and patients with actionable tumour alterations were then eligible for phase II treatment arms with targeted therapies. Patients of age 15 to 21 years comprised more than 40% of screened patients. The study team described the frequency and spectrum of alterations detected in the first 1,000 patients screened and the experience with treatment arm assignment and enrolment for children and young adults with advanced cancers.

Tumours from patients old 1 to 21 years with refractory solid tumours, 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 enrolment were compared between clinical and demographic groups.

Testing was completed for 94.7% of tumours. Actionable alterations were detected in 31.5% of the first 1,000 tumours screened, with treatment arm assignment and enrolment occurring in 28.4% and 13.1% of patients. Assignment rates varied by tumour histology and were higher for patients with CNS tumours or enroled at Pediatric Early Phase Clinical Trials Network sites.

A reported history of prior clinical molecular testing was associated with higher assignment and enrolment rates. Actionable alterations in the MAPK signalling pathway were most frequent (11.2%). The most common reasons provided for not enroling on treatment arms were patients receiving other treatment or poor clinical status.

The authors concluded that their data support the early use of tumour molecular screening for paediatric and young adult patients whose tumours have not responded to standard treatments.

They also commented that the study design has several limitations suggesting opportunities to increase the rate of actionable alteration detection and enrolment in clinical studies. Alternative approaches would be necessary to more comprehensively identify inactivating events (deletions and splice site mutations) in tumour suppressor genes and fusion events between oncogenes and novel or uncommon partners. More comprehensive analysis (including exome, whole genome, and transcriptome sequencing) will provide further insight into the additional yield of those approaches for identification of molecular targets. Determination of alteration actionability made in real time would facilitate the use of molecular profiling results from outside laboratories, increasing study access for patients without available tumour for testing, an approach that will be implemented in Pediatric MATCH in 2022.

In a minority of cases, alterations were classified as non-actionable in Pediatric MATCH that could be considered actionable for agents not included in the study, including biomarkers for therapies approved by US Food and Drug Administration and molecular targets of investigational agents. A review of the most frequently identified non-actionable alterations detected also serves as a reminder that many of the most frequent genomic events in paediatric solid tumours remain therapeutic challenges.

The study was presented in part at the ASCO 2021 Annual Meeting.

It was supported by the NCI of the US National Institutes of Health and by The St Baldrick’s Foundation.


Parsons DW, Janeway KA, Patton DR, et al. 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. JCO; Published online 30 March 2022. DOI: 10.1200/JCO.21.02838