Although 84% of children with cancer survive 5 years or more, children with refractory, relapsed, and progressive high-risk malignancies have a poor median survival of 9.5 months. The German INFORM registry is a large prospective, noninterventional, multicenter study collecting clinical and molecular data on pediatric patients with refractory, relapsed, and progressive malignant cancers. The study is evaluating the clinical potential of precision oncology in children by identifying molecular targets for off-label treatment and identifying potential biomarkers for clinical trials.

According to results from the study, presented by van Tilburg et al at the ASCO20 Virtual Scientific Program and featured in a press briefing prior to the meeting (Abstract LBA10503), pediatric precision oncology in a real-world, multinational setting is feasible. The prioritization algorithm used in the study identified therapeutic options for subgroups of children and offered important new diagnostic information to families.

Study Methodology

Eight countries participated in the INFORM registry, which was developed by a consortium of pediatric oncologists and genomics researchers. Patients with refractory, relapsed, and progressive malignant cancers, including primary cancers, are eligible to enroll in the study.

The researchers collected DNA information, including germline DNA from fresh-frozen tumor material, and performed whole-exome sequencing, low-coverage whole-genome sequencing, RNA sequencing, RNA expression array, and DNA methylation on the samples. An interdisciplinary molecular board met online weekly and reviewed and prioritized alterations based on a seven-step scale ranging from “very high” to “very low,” depending on the type of alteration and its entity-specific relevance.

The study enrolled more than 1,300 patients. The median age of the children participating in the study was 12 years. Average turnaround time from submission to report was 25.4 days.

Study Results

The distribution of the highest priority target per patient was: very high, 8.0%; high, 14.8%; moderate, 20.3%; intermediate, 23.6%; borderline, 14.4%; low, 2.5%; very low, 1.0%; and no actionable target, 15.4%.

Based on these results, 149 patients received targeted treatment on the basis of identified targets, of which 20 had a very high–priority target (mostly ALK, BRAF, and NRAS mutations, and MET and NTRK fusions). Patients in this group had a median progression-free survival of 204.5 days (95% confidence interval [CI] = 91.0–628.0) compared to 114 days (95% CI = 103–133) for all other 505 patients (P = .0095).

There were no clinically relevant differences in overall survival. Explorative analysis of the time to progression ratio (before compared to after enrollment) showed that patients treated according to a very high–priority target had a higher time to progression ratio (1.0) compared to all other patients (0.7). Possible predisposition syndromes were identified in 7.8% of patients, half of which were newly diagnosed. Methylation analysis provided a diagnosis refinement in 8% of central nervous system tumors.

“Pediatric precision oncology in a real-world, multinational setting is feasible. The prioritization algorithm identifies subgroups benefiting from molecularly matched targeted treatment. Still, for patients without a very high–priority target, further layers of molecular and functional data should be incorporated in future programs,” concluded the study authors.

Commentary

The study’s findings show that it is possible to identify precision targets in pediatric patients with relapsed cancers that can guide clinical decision-making regarding treatment approaches.

“This registry has opened up the genomic landscape in pediatric oncology,” said first study author Cornelis van Tilburg, MD, PhD, a pediatric oncologist at Hopp Children’s Cancer Center Heidelberg, in a statement. “Compare this to adult oncology, where there are many new trials, many new biomarkers, and many new drugs. Pediatric oncology is really lagging behind when it comes to precision medicine and the development of new drugs.”

Richard L. Schilsky, MD, FACP, FSCT, FASCO

“This study shows the potential of precision medicine to extend survival for our most precious population of patients with cancer—children,” said Richard L. Schilsky, MD, FACP, FSCT, FASCO, Chief Medical Officer and Executive Vice President of ASCO, in a statement. “In our list of Research Priorities to Accelerate Progress, ASCO noted the importance of moving precision medicine into the care of pediatric patients. These early results provide the basis for continued research into this area.”

Disclosure: Funding for this research was provided by German Cancer Aid, German Childhood Cancer Foundation, Ein Herz für Kinder Foundation, and the German Cancer Consortium. For full disclosures of the study authors, visit coi.asco.org.