A prioritization algorithm has identified subgroups of pediatric oncology patients who can benefit from molecularly matched targeted therapies. This approach extended the time until disease progression by 3 months for a small group of poor prognosis pediatric patients with very high-priority targets.
Children with refractory, relapsed, and progressive high-risk malignancies have a poor survival of less than 20 percent and 9.5 months median survival. The new study evaluated the clinical potential of precision oncology in children by identifying molecular targets for off-label treatments and potential biomarkers for enrollment and development of clinical trials, as well as providing additional diagnostic precision.
The INdividualized Therapy FOr Relapsed Malignancies in Childhood (INFORM) study "gives children a chance to benefit from off-label therapy, sometimes from adult oncology, targeted drugs, and enrollment in biomarker-driven clinical trials. This is the first time clinical outcome in a real-world setting of a large-scale, multinational personalized pediatric oncology platform was assessed for clinical benefit," said lead author Cornelis van Tilburg, MD, PhD, a pediatric oncologist at Hopp Children's Cancer Center Heidelberg. He presented the study's findings during the virtual scientific program of the ASCO 2020 Annual Meeting (Abstract LBA10503).
While current treatment of childhood cancers results in high overall cure rates, relapsed high-risk disease is associated with a poor prognosis. For the most part, precision oncology has yet to be applied in pediatric cancer care, unlike in adult cancer where it has improved outcomes.
"For pediatric patients, if the cancer has relapsed, the prognosis is poor and there are few new innovative treatments," said van Tilburg. "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."
Study Design
The INFORM registry was developed by a consortium of pediatric oncologists and genomics researchers from eight countries and 72 sites to develop precision medicine-based approaches and to assess their efficacy across high-risk relapsed or therapy refractory pediatric cancers. The registry collected clinical and molecular data from fresh frozen tumor material of 526 pediatric patients, median age 12 years.
The seven-step algorithm prioritized molecular alterations or affected pathways, which would theoretically be targetable by an approved drug or an investigational agent. The priority levels were based on characteristics such as druggability, genetic change/expression, and direct drug target/pathway activation.
Using the algorithm, the researchers identified subgroups of patients with genomic or molecular characteristics ranging from highest priority for pairing with a targeted drug to no actionable target. Treating oncologists had access to and could use the molecular target information for clinical decision-making. In addition, INFORM provided important diagnostic information like underlying cancer predisposition syndromes and diagnostic refinements in brain tumors.
Research Findings
When grouped by the highest priority target for each patient, ranging from molecular alterations to changes in gene expression in molecular pathways important to cancer development and survival, 8 percent of patients had a very high-priority level target, followed by high (14.8%), moderate (20.3%), intermediate (23.6%), borderline (14.4%), low (2.5%), and very low (1%) priority, and no actionable target (15.4%).
A total of 149 patients received targeted treatment based on the targets identified using the algorithm at the discretion of their clinical pediatric oncologist. Twenty patients had a very high-priority level target-mainly ALK, BRAF, and NRAS mutations and MET and NTRK fusions.
"Children with a very high priority level target who received a matching drug showed longer progression-free survival of 204.5 days compared to 114 days for all other children," said van Tilburg. There were no clinically relevant differences in overall survival.
The findings show that it is possible to identify precision targets in relapsed pediatric cancers that can guide clinical decision-making about treatment approaches. "This registry has opened up the genomic landscape in pediatric oncology," said van Tilburg. "It provides a unique source of information to help match new drugs or drug ideas with suitable biomarkers in certain pediatric patient populations."
The researchers plan to continue to analyze data from the registry using the algorithm. Additional molecular and functional analyses are being implemented for the registry, including ex vivo drug screens on viable tumor material and complex biomarker algorithms. In addition, based on the results obtained from the INFORM registry, a series of biomarker-driven phase I/II trials (called INFORM2) has been launched.
In conclusion, van Tilburg noted, "Pediatric precision oncology in a real-world, realistic time frame, multinational setting is feasible. Very high priority targets identified by INFORM provided therapeutic opportunities for subgroups of children. Important new diagnostic information could be offered to children and families, such as predisposition syndrome and diagnostic refinements in brain tumors."
In terms of future outlook, he said, "there is a dire need for biomarker-driven pediatric intervention trials. A significant group of patients did not have very high level targets. We should put efforts into adding in layers of diagnostics to also let them benefit from new treatments."
Richard L. Schilsky, MD, ASCO's Chief Medical Officer and Executive Vice President, commented: "This study shows the potential of precision medicine to extend survival for our most precious population of patients with cancer-children. 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."
Mark L. Fuerst is a contributing writer.