Two Pediatric Trials Find Targets for Treatment-Refractory Cancers

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An interim analysis of the large Pediatric MATCH trial found that 24% of children and young adolescents with cancers refractory to current treatments had been assigned to treatment with investigational targeted study agents based on genetic alterations detected in their tumors,1 which is more than double a previous estimate of about 10%. In tandem with the announcement of these findings, an unrelated preliminary study suggested that the targeted agent entrectinib appears active in treatment-refractory central nervous system tumors, neuroblastoma, and other solid tumors in pediatric and young adult patients with cancers that harbor fusions in NTRK1/2/3, ROS1, or ALK genes.2

Taken together, these studies demonstrate the potential for genetic sequencing of children and young adults with treatment-refractory cancers to identify potential genetic alterations for targeted therapies with potential benefit in these otherwise untreatable cancers. Other studies using this approach are ongoing. Both studies were featured at a press briefing in advance of the 2019 ASCO Annual Meeting and were formally presented at the meeting.1,2

Monica M. Bertagnolli, MD, FACS, FASCO

Monica M. Bertagnolli, MD, FACS, FASCO

Commenting on the Pediatric MATCH trial, ASCO President Monica M. Bertagnolli, MD, FACS, FASCO, said: “Congratulations to the study team on this wonderful work. There were considerable logistics involved, which were achieved by a [National Cancer Institute]–funded mechanism. We are eager to see the downstream effects of treatment based on this approach. These results bring us one step closer to bringing the precision medicine era to pediatric cancer care. Now that we know that targetable genetic alterations are fairly common in pediatric cancer, we have an exciting opportunity to boost success rates.”

Regarding the entrectinib trial, Dr. Bertagnolli said: “There have been far fewer studies of targetable cancer medicines in pediatric populations than in adults. Although these data are early and more research is needed, they suggest the exciting possibility of the first treatment for childhood cancers that is effective based on tumor genetics instead of tumor types or location.”

Pediatric MATCH Trial: Study Details

The National Cancer Institute (NCI)-Children’s Oncology Group Pediatric Molecular Analysis for Therapy Choice (NCI-COG Pediatric MATCH) trial was launched in 2017. At the time, it was estimated that genetic sequencing would identify about 10% of treatment-refractory cancers with genetic alterations amenable to treatment with an investigational targeted therapy. However, this interim analysis suggests that at least twice as many such tumors can be found using this approach.

Our study shows that we can successfully create a nationwide molecular screening trial for children, adolescents, and young adults with cancer that has been resistant to treatment.
— Donald Williams “Will” Parsons, MD, PhD

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“Our study shows that we can successfully create a nationwide molecular screening trial for children, adolescents, and young adults with treatment-resistant cancers. One of our key goals has been to expand access to targeted therapies for pediatric patients with cancer across the country, and these early results suggest that goal is being achieved,” said lead author and COG study chair, Donald Williams “Will” Parsons, MD, PhD, Associate Professor of Pediatrics-Oncology at Baylor College of Medicine, Houston.

Dr. Parsons noted that pediatric trials of targeted treatments and the adoption of targeted therapies for pediatric patients with cancer have lagged behind those for adults. Only a small number of targeted agents are approved for the treatment of pediatric cancers compared with more than 150 approvals for targeted therapies in adult cancers.

Pediatric MATCH is the first nationwide pediatric precision oncology trial for patients with cancers that have not responded to standard treatments. The goals of the study are to identify the specific genetic alterations occurring in patients’ cancers by genetic screening, match patients to drugs targeted to those genetic alterations, and evaluate the impact of those treatments in corresponding phase II Pediatric MATCH trials.

At the time of the interim analysis, 422 children, adolescents, and adults between the ages of 1 and 21 were enrolled at more than 100 sites across the United States. Of these patients, 101 (24%) had brain tumors, 300 (71%) had other solid tumors, and 21 (5%) had lymphomas or histiocytic disorders. “Patients had more than 60 different diagnoses,” Dr. Parsons noted.

Tumor samples from 390 patients were sequenced for more than 160 genes that could match patients to 1 of the 10 investigational targeted therapies listed here:

  • Larotrectinib (targets NTRK fusions)
  • Erdafitinib (targets FGFR alterations)
  • Tazemetostat (targets EZH2, SMARCB1, and SMARCA4 mutations)
  • LY3023414 (targets the PI3K/mTOR pathway)
  • Selumetinib (targets the MAPK pathway)
  • Ensartinib (targets ALK or ROS1 mutations)
  • Vemurafenib (targets the BRAF V600E variant)
  • Olaparib (targets defects in DNA-damage repair)
  • Palbociclib (targets cell-cycle genes, including the BRCA, RAS, and CDK families, among many others)
  • Ulixertinib (targets the MAPK pathway, including mutations in BRAF, GNAQ, NF1, and RAS family genes).

“Pediatric MATCH provides a national framework for molecularly screening patients. Any new targeted therapies that are developed can fit into the framework,” Dr. Parsons explained.

Pediatric MATCH Trial: Key Findings

Tumor testing of 390 patients (92%) identified mutations, fusions, or gene copy number changes amenable to treatment with 1 of the 10 agents in 112 patients (29%). Of these patients, 24% had a treatment assigned, and 10% were enrolled on 1 of the protocols in the phase II Pediatric MATCH trials (41% of matched patients). The median time to treatment assignment was 15 days. Other matched eligible patients could enroll at a later date.

Tumor testing revealed targetable alterations in more than 40% of patients with brain tumors and more than 26% of patients with other cancer types, including both common and rare cancers. For example, 74% of patients with astrocytomas had a genetic alteration that was targetable. Detection rates were not significantly related to patient age.

Targeting Cancer Genetic Alterations

  • The Pediatric MATCH trial found that 29% of recurrent or refractory solid tumors harbored targetable genetic alterations, with 24% of patients matched to a treatment arm.
  • This rate is more than double the expected rate of such tumors.
  • A preliminary study showed activity for therapy targeted with entrectinib to three genetic alterations in recurrent or refractory pediatric solid tumors.

The most common targetable alterations included RAS gene mutations (16 patients), BRAF mutations or fusions (14 patients), SMARCB1 mutations or deletions (14 patients), NF1 mutations (11 patients), and a number of other alterations occurring in fewer than 10 patients each.

The study is continuing to evaluate tumor samples and blood samples. Anticipated enrollment is 1,000 patients. New targeted therapies will be added as they become available. In the future, combination strategies may be studied, the authors said.




Nita Seibel, MD

Nita Seibel, MD

NCI Chair of the study, Nita Seibel, MD, Head of Pediatric Solid Tumor Therapeutics in the Clinical Investigations Branch of NCI’s Cancer Therapy Evaluation Program, reminded listeners of the collaborative nature of this effort: “Pediatric MATCH depends on active partnership among NCI, COG, the U.S. Food and Drug Administration, pharmaceutical companies, and other key pediatric cancer research stakeholders.”

Entrectinib Phase I/IB Trial: Study Details

Entrectinib, at present not included in the Pediatric MATCH phase II trials, is an oral drug that penetrates the central nervous system and inhibits protein pathways related to mutations in NTRK1/2/3, ROS1, and ALK genes. Promising activity has been observed with entrectinib in adults with these target rearrangements.

“A variety of pediatric cancers harbor these alterations and changes. The list is growing, and these changes are emerging in unexpected cancers,” said Giles W. Robinson, MD, a pediatric neuro-oncologist at St. Jude Children’s Research Hospital, Memphis.

A small phase I/IB study of 29 pediatric and young adult patients with recurrent or refractory rare central nervous system tumors, neuroblastoma, or other solid tumors suggests that entrectinib can achieve responses in cancers that harbor these genetic alterations. Responses were observed in 12 of 28 evaluable patients, who were between the ages of 4.9 months and 20 years (median age = 13 years).

Our results show that children with life-threatening cancers can benefit greatly [from targeted therapies], even after other conventional therapies have not worked.
— Giles W. Robinson, MD

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“Our results show that children with life-threatening cancers can benefit greatly, even after other conventional therapies have not worked. We’ve seen some rapid and durable responses, which is gratifying. These early findings suggest that this therapy holds great promise for those whose tumors have these specific gene fusions,” said Dr. Robinson, lead author of the phase I/IB study.

The data reported at the meeting were based on 29 patients enrolled in STARTRK-NG. Most of the patients with central nervous system tumors had surgery followed by radiation therapy. Other tumor types included neuroblastoma and solid tumors. The first phase of the trial identified optimal dosing; the second phase was expanded to include patients with tumors harboring alterations in NTRK1/2/3, ROS1, and ALK genes, which were present in 12 of the 29 patients.

Entrectinib Phase I/IB Trial: Key Findings

Objective responses were documented in 12 patients treated with entrectinib, for a median duration of treatment of 281 days. The median time to response was 57 days. All responses occurred at doses of at least 400 mg/m2. No responses were observed in patients whose tumors did not express the genetic alterations targeted by entrectinib.

When the investigators digged deeper into response according to tumor types, they found that all five of the evaluable patients with central nervous system tumors had an objective response: one complete response and four partial responses. One remaining patient had not been evaluated at the time of study presentation. Six patients with extracranial tumors had responses: one complete response and five partial responses. One patient with neuroblastoma had a complete response.

“It gives me great pleasure to show you the intracranial responses,” Dr. Robinson told listeners. “These cancers would be universally fatal if the patients had not responded to the drug. Tumors disappear or shrink significantly,” he added.


For interviews with a host of experts who presented their study findings at the 2019 ASCO Annual Meeting, visit The ASCO Post Newsreels at

At the recommended pediatric dose of 550 mg/m2 once daily, side effects included fatigue, elevated creatinine levels, and dysgeusia; one incidence of pulmonary edema occurred at the higher dose. Weight gain was also observed. The recommended dose for children unable to swallow is 400 mg/m2 once daily.

The trial continues to accrue patients, and phase II testing will soon be initiated.

The study was funded by F. Hoffmann La-Roche Ltd, and the design and conduct of the study were also supported by Alex’s Lemonade Stand Foundation for Childhood Cancer. 

DISCLOSURE: Dr. Bertagnolli has a leadership role in Leap Therapeutics; is a consultant/advisor with Syntalogic; has received institutional research funding from AbbVie, Agenus, Astellas Pharma, AstraZeneca, Breast Cancer Research Foundation, Bristol-Myers Squibb, Celgene, Complion, Exelixis, Genentech, GHI Pharma, Gilead Sciences, GlaxoSmithKline, Incyte, Jazz Pharmaceuticals, Lilly, Matrex, Mayo Clinic, MGH, Millennium Pharmaceuticals, Novartis, Patient-Centered Outcomes Research Institute, Pfizer, Robert Wood Johnson Foundation, SageRock Advisors, Taiho Pharmaceutical, Bayer Health, Eisai, Leidos, Lexicon, Merck, Pharmacyclics, Takeda, Tesaro, Baxalta, Sanofi, Teva, Janssen, and Merck. Dr. Parsons disclosed participation in royalty sharing associated with patents related to cancer genes discovered through sequencing of several adult cancer types. Dr. Seibel reported no conflicts of interest. Dr. Robinson has financial ties with Lilly, Novartis, Genentech/Roche, and Novartis.


1. Parsons DW, Janeway KA, Patton D, et al: Identification of targetable molecular alterations in the NCI-COG Pediatric MATCH trial. 2019 ASCO Annual Meeting. Abstract 10011. Presented June 2, 2019.

2. Robinson GW, Gajjar AJ, Gauvain KM, et al: Phase 1/1B trial to assess the activity of entrectinib in children and adolescents with recurrent or refractory solid tumors including central nervous system tumors. 2019 ASCO Annual Meeting. Abstract 10009. Presented June 2, 2019.