Dealing With Disease
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Genomic sequencing allowed 107 relapsed pediatric cancer patients to receive a matched targeted therapy that was not considered standard of care, according to recent data from an international clinical trial.

The study was published in Cancer Discovery and the senior author was Birgit Geoerger, a professor of pediatric clinical research at Gustave Roussy Cancer Center in France.

“The main purpose was to genetically profile the patients’ tumors and use that to suggest a treatment,” said Geoerger, “Are there molecular alterations that we can target with these newer drugs?”

Pediatric cancers have a high rate of remission, with 85 percent of patients surviving five years or longer after diagnosis. However, if the cancer returns, treatment options are limited. Though tumors often undergo gene panel sequencing, this information is not regularly used to guide treatment decisions. “There are not a lot of trials testing targeted therapies in children,” Geoerger said.

So she and colleagues initiated the Molecular Profiling for Pediatric and Young Adult Cancer Treatment Stratification (MAPPYACTS) trial, a European international prospective precision medicine study.

MAPPYACTS prospectively recruited pediatric patients with relapsed cancers and then performed comprehensive whole exome sequencing (WES) and/or RNA sequencing in order to match patients to therapies. The researchers collected tissue samples from 774 patients, 632 of which were successfully sequenced. A clinical molecular tumor board then reviewed the sequencing data from each patient.

Mutations were considered “ready for routine use” if there was significant clinical evidence that a drug could effectively treat tumors harboring the variant. Mutations were considered “potentially actionable” if any evidence existed that an approved or investigational drug could target the mutated protein or another member of the affected signaling pathway.

The clinical molecular tumor board identified 432 patients with potentially actionable alterations, 107 of whom were then treated with a matched targeted therapy, either alone (57 percent), in combination with chemotherapy (37 percent), or in combination with another targeted therapy (11 percent).

The majority of cancers with “ready for routine use” mutations were tumors of the central nervous system, such as gliomas and medulloblastomas, or anaplastic large cell lymphomas.

Notably, 42 percent of the “ready for routine use” alterations found in this study were previously unknown or had not been identified by previous diagnostics. Geoerger said that, “It didn’t mean an alteration couldn’t be found, rather that nobody looked for it.”

The overall response rate of patients who received a matched therapy was 17 percent, with a 41 percent disease control rate. Among patients with alterations ready for routine use, all of whom received their treatments as a monotherapy, the objective response rate was 38 percent. Patients with potentially actionable mutations that were not ready for routine use had an overall response rate of 14 percent.

The researchers also investigated the possibility of using circulating tumor DNA (ctDNA) to identify targetable mutations. Though the team did not make treatment decisions based on this arm of the study, they successfully performed WES on ctDNA from 128 patients with matched tumor WES and found 94 potentially actionable mutations, 35 of which had not been detected by tumor WES. Sequencing of ctDNA also successfully identified 76 percent of potentially actionable alterations that were found in tumor tissue.

Overall, Geoerger feels that this study provides evidence for widespread genetic sequencing of pediatric cancers and the matching of patients’ tumor genetic profiles with targeted therapies and combinations.

“Our recommendation would be to have a sequencing panel for the ‘ready for routine use’ mutations and fusions,” Geoerger said. “Nearly everybody should have that as part of their diagnostic setup.”

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