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Pediatric Precision Oncology Study Matches 28 Percent of Patients to Targeted Therapies

NEW YORK – A pediatric cancer study assessing the feasibility of precision oncology for pediatric patients in a real-world setting found that about 28 percent of refractory, relapsed, and progressive high-risk pediatric cancer patients with poor prognosis were able to be treated with targeted therapies.

At the American Society of Clinical Oncology's virtual annual meeting, pediatric oncology physician and researcher Cornelis van Tilburg of the Hopp Children's Cancer Center in Heidelberg presented findings from the INFORM — Clinical Outcome and Benefit From Molecular Subgroups study, a prospective, noninterventional, multicenter, multinational feasibility registry study analyzing the efficacy of pediatric precision oncology in the real world. In a total cohort of 526 patients, 149 received targeted therapies.

Although INFORM wasn't a clinical trial, its findings echoed the interim analysis of the National Cancer Institute-Children's Oncology Group (NCI-COG) Pediatric Molecular Analysis for Therapy Choice (MATCH) study — a precision medicine clinical trial for pediatric cancer — which found in May 2019 that 24 percent of participants were eligible to receive treatment with a targeted therapy.

For INFORM, van Tilburg and his colleagues were investigating the clinical utility of a molecular target priority algorithm to see if it could identify subgroups of pediatric patients who might benefit from targeted therapies. They were also aiming to identify potential biomarkers for clinical trials and provide additional information to make diagnoses more precise.

Doctors from 72 sites in eight European countries submitted fresh, frozen tumor and blood for germline analysis from their patients with refractory, relapsed, progressive malignant disease for the study, van Tilburg said, noting that cases who were at exceptionally high risk at primary diagnosis could also participate in the study. Patients had to have their primary diagnosis before the age of 21.

The researchers then performed genome sequencing, exome sequencing, RNA sequencing, gene expression analysis, and 850K methylation profiling to identify any genetic alterations in the patients' tumors. The alterations were then discussed on a weekly basis by an online interdisciplinary molecular tumor board, which also included the treating physicians.

All identified alterations were entered into a remote database alongside clinical information for the patients, and the treating physician could use the molecular information for clinical decision-making, van Tilburg said.

From January 2015 to Oct. 1, 2019, 1,043 patients were registered. Some of these patients were not eligible, or their samples were unsuitable for molecular analysis, leaving the researchers with 919 patients. Of those 919, 393 were alive at the time the study was ended and their follow-up was still ongoing, so they were excluded from this analysis. This left the team with 526 patients, with a completed follow-up of at least two years. Of these patients, 149 received targeted drugs and 377 did not.

The algorithm evaluated each molecular target according to a scale of seven priority levels from very low to very high. It assigned a level based on the target's druggability, alteration type, or how much evidence there was for that target's relevance.

"The patients who received matching targeted drugs had relatively more very high and high priority-level targets, as compared to patients who didn't, which shows us that treating physicians treated patients according to our target algorithm," van Tilburg said. Once the algorithm identified very high, high, or moderate targets, physicians were more likely to use that data to make matching treatment decisions. The patients who received no matching treatment were those in the group with a larger number of intermediate, borderline, or low target priorities, or those with no match at all.

Additionally, van Tilburg said, 17 children were moved to clinical trials, and 40 children were found to have potential cancer predisposition syndromes, 17 of whom were previously unaware of the presence of these syndromes. The researchers' methylation profiling analyses also provided diagnostic refinement for about 8 percent of the brain tumors that were included in the analysis, and they are evaluating additional molecular diagnostic refinement methods in the sarcoma group patients, he added.

Most importantly, however, the 20 pediatric patients who landed in the very high priority group and who received targeted therapies showed a much better median progression-free survival of 204 days as compared to 114 days for the patients who didn't received target therapies, van Tilburg said. Most of the 20 children in the very high priority group were diagnosed with neuroblastomas, but several had high-grade gliomas with ELK mutations and fusions. There were also some other diagnoses with fusions and several mutations present, he added.

What INFORM really shows, van Tilburg noted, is that pediatric precision oncology is feasible in a real-world multinational setting. "The prioritization algorithm identified subgroups benefiting from treatment with matched drugs," he said. "We were able to identify germline alterations, which is, of course, important for patients and families. We were unable to provide more diagnostic precision and are evaluating this in the near future."

Further studies are needed with larger groups of high priority-level target patients, he added, as well as added layers of molecular and functional data such as functional drug sensitivity profiling, proteomics, and liquid biopsy. "And, last but not least, there is an urgent need for biomarker-driven pediatric interventional clinical trials, like INFORM-2, Pediatric MATCH, ESMART, and so on," van Tilburg said.

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