Genomic Era Reaches Pediatric Oncology

Meir Rinde
Published: Tuesday, Sep 04, 2018
Rajen Mody, MBBS

Rajen Mody, MBBS

The relative rarity of pediatric cancers has hampered the work of uncovering their causes and developing new therapies, but efforts to expand the use of genomic and biomarker testing are beginning to provide new options for children and their families, as well as more information to help tailor therapeutic plans.

In particular, investigators are looking to target markers that may occur in multiple tumor types in hopes of finding better treatments for recurring and refractory disease and for rare cancers that carry poor prognoses.

A prime example of this trend is larotrectinib (LOXO-101), a pan-TRK inhibitor with FDA priority review status for adult and pediatric patients with locally advanced or metastatic solid tumors with oncogenic fusions involving TRK proteins, which are encoded by NTRK genes. In a trial including pediatric patients with infantile fibrosarcoma, other soft issue sarcomas, and papillary thyroid cancer, larotrectinib induced an objective response rate (ORR) of 93% in those with TRK fusion–positive malignancies (n = 15).1 The median age of patients in the cohort was 4.5 years (range, 1 month-18 years).

NTRK is a very good target. It is driving so much of a tumor’s growth that when you treat, it impacts the tumor’s clinical behavior. It’s not a very frequent target, but it’s clearly a very clean target,” said Rajen Mody, MBBS, a pediatric oncologist at the University of Michigan C.S. Mott Children’s Hospital in Ann Arbor.

Larotrectinib has excited interest not only because of its efficacy and the fact that it is one of the first agents developed as a “tumor-agnostic” drug, but also because its developer, Loxo Oncology, took the unusual step of including both adult and pediatric patients in the first trials. TRK fusions are rare, occurring in about 0.5% to 1% of cancers overall, and Loxo had to cast a wide net to populate its trials with patients who harbored the abnormality.

Larotrectinib’s development suggests a path that more new agents could take. It also points to the importance of expanding molecular marker testing of pediatric cancers and including both investigational and existing drugs in young patients in clinical trials, oncologists said.

The National Cancer Institute (NCI) and the Children’s Oncology Group (COG) have mounted a major effort to apply genomic principles to drug development for children and adolescents aged 1 to 21 years with the Pediatric MATCH trial. The study is testing 9 targeted therapies simultaneously in refractory solid tumors in approximately 200 cancer centers in the United States (Figure).2

“By definition, any pediatric tumor is an orphan disease. Now all of sudden people are realizing that with these molecularly targeted agents, there’s a very, very small subgroup of patients who are going to have the marker, and they want to find the small populations,” said Julia L. Glade Bender, MD, vice chair of pediatric clinical research at Memorial Sloan Kettering Cancer Center in New York, New York. “If you’re looking for the needles in the haystacks, you need more haystacks.”

Figure. Targeted Therapies Explored in Pediatric MATCH Trial2



Pediatric cancers make up less than 1% of diagnosed cancers. In children up to 14 years old, leukemias and tumors of the brain and central nervous system are most common, followed by neuroblastoma, Wilms tumor of the kidney, lymphomas, rhabdomyosarcoma, retinoblastoma, and bone cancers (osteosarcoma and Ewing sarcoma).3 More than 80% of children with cancer survive 5 years or more, but survival rates are poor for those with certain diseases such as diffuse intrinsic pontine glioma and sarcomas with metastatic disease.4

The different biology of tumors in children and adolescents creates both special challenges for research on precision oncology and possible opportunities, said Eugene Hwang, MD, a pediatric neuro-oncologist at Children’s National Medical Center in Washington, DC. “Mutations in children tend to be on the order of a magnitude fewer than they are in adults. In some ways that hurts us because we don’t actually have a lot of different mutations to go after,” he said. “In some ways maybe you could say that might help us because anything that’s there is more likely to be important than it is in an adult cancer that has so many mutations, where maybe you have too many targets to choose from and not all of them are important.”


View Conference Coverage
Online CME Activities
TitleExpiration DateCME Credits
Medical Crossfire®: Key Questions for the Use of Immunotherapy Throughout the Disease Continuum for NSCLC in an Era of Rapid DevelopmentSep 29, 20181.5
Provider and Caregiver Connection™: Addressing Patient Concerns While Managing GlioblastomaSep 29, 20182.0
Publication Bottom Border
Border Publication
x