Despite advances in treatment for pediatric patients, cancer remains the primary cause of disease-related mortality in children and adolescents. Data from the international clinical trial MAPPYACTS, which aims to define tumor molecular profiles in pediatric patients with recurrent/refractory malignancies, showed that genomic sequencing of tumors enabled 107 pediatric patients to receive an appropriate matched therapy that was not the standard of care. Overall, matched treatment resulted in a 17% objective response rate. The study by Berlanga et al, published in Cancer Discovery, underlines the feasibility of molecular profiling at cancer recurrence and demonstrates the benefit for patients with selected key drivers.

Study Methodology

From 2016 to 2020, researchers collected tissue or blood samples from 774 patients in France, Italy, Ireland, and Spain, 632 of which were successfully sequenced through whole-exome sequencing and/or RNA sequencing to determine a specific targeted therapy for each patient. 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 mutation. Mutations were considered “potentially actionable” if there was evidence that an approved or investigational drug could target the mutated protein or another member of the affected signaling pathway. At least one genetic alteration leading to a targeted treatment suggested was identified in 436 patients (69%) with successful sequencing; 10% of these were considered “ready for routine use.” Of 356 patients with follow-up beyond 12 months, 107 (30%) received one or more matched targeted therapies.

Results

The researchers found that 42% of the “ready for routine use” alterations discovered in the study were previously unknown or had not been identified by previous diagnostics. The majority of cancers with “ready for routine use” mutations were central nervous system tumors, including gliomas and medulloblastomas, or anaplastic large-cell lymphomas.

Overall, matched treatment resulted in a 17% objective response rate, with a 41% 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%. Patients with potentially actionable mutations that were not ready for routine use had an overall response rate of 14%.

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

Clinical Significance

According to the study authors, the results from the MAPPYACTS clinical trial underlie the feasibility of molecular profiling at cancer recurrence in children on a multicenter international level and demonstrate clinical benefit for patients with selected key drivers.

“The use of circulating cell-free DNA deserves validation in prospective studies. Our study highlights the need for innovative therapeutic proof-of-concept trials that address the underlying cancer complexity,” concluded the study authors.

Disclosure: Funding for this study was provided by the Institut National du Cancer, Fondation ARC, Association Imagine for Margo, Fédération Enfants et Santé, Société Française de Litte Contre les Cancers et les Leucémies de l’Enfant et l’Adolescent (SFCE), Dell, Annenberg Foundation, Association Hubert Gouin—Enfance et Cancer and Meghanora, Fundación FERO and Fundación Rotary, and Gustave Roussey Cancer Center. For full disclosures of the study authors, visit aacrjournals.org/cancerdiscovery.