Precision oncology approach confers clinical benefit in relapsed pediatric cancer
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An algorithm designed to identify molecular targets for precision therapy extended time to disease progression for pediatric patients with relapsed cancer, according to study results presented during the ASCO20 Virtual Scientific Program.
“Children with refractory, relapsed and progressive high-risk malignancies have poor survival of less than 20%,” Cornelis van Tilburg, MD, PhD, pediatric oncologist at Hopp Children’s Cancer Center in Germany, said during a presentation. “[This trial] gives children a chance to benefit from off-label targeted drugs and [allows for] enrollment in biomarker-driven clinical trials.”
Although pediatric precision oncology programs have identified molecular actionable variants, the clinical benefit has not been clearly established.
Van Tilburg and colleagues developed the Individualized Therapy for Relapsed Malignancies in Childhood (INFORM) registry to help develop precision medicine-based approaches and to analyze their effectiveness across high-risk relapsed or refractory pediatric cancers.
Researchers collected clinical and molecular data of 525 patients (median age, 12 years; range, 0-40) with refractory, relapsed or progressive malignant disease. Fresh frozen tumor material underwent whole-exome sequencing, low coverage whole-genome sequencing, RNA sequencing, RNA expression array and DNA-methylation.
The investigators used a seven-step algorithm that prioritized molecular alterations or affected pathways potentially targetable by an approved or investigational drug. Priority levels, ranging from “very high” to “very low,” were based on certain characteristics, including druggability, genetic change or expression and direct drug target or pathway activation.
Researchers grouped patients by the highest priority target, ranging from molecular alterations to changes in gene expression in molecular pathways that are key to cancer development and survival. In all, 8% had a very high-priority target, 14.8% had a high-priority target, 20.3% had a moderate-priority target, 23.6% had an intermediate-priority target, 14.4% had a borderline-priority target, 2.5% had a low-priority target, 1% had a very low-priority target and 15.4% had no actionable target.
Among all patients, 149 received targeted treatment based on targets identified using the algorithm, including 20 patients with very high-priority targets. Most of these targets were ALK, BRAF and NRAS mutations, as well as MET and NTRK fusions.
Results showed median PFS of 204.5 (95% CI, 91-628) days among patients with very high-priority targets compared with 114 (95% CI, 103-133) days among the other 505 patients (P = .0095).
Researchers observed no clinically relevant OS difference between the two groups.
An explorative analysis showed patients with very high-priority targets had a higher time to progression ratio (1.0) than all other patients (0.7).
Researchers identified possible predisposition syndromes among 7.8% of patients, half of which were newly diagnosed.
Methylation analysis yielded a diagnosis refinement in 8% of central nervous system tumors.
“This registry has opened up the genomic landscape in pediatric oncology,” van Tilburg said. “It provides a unique source of information to help match new drugs or drug ideas with suitable biomarkers in certain pediatric patient populations.” – by John DeRosier
References:
van Tilburg C, et al. Abstract LBA10503. Presented at: ASCO20 Virtual Scientific Program; May 29-31, 2020.
Disclosure: van Tilburg reports consultant/advisory roles with Bayer and Novartis. Please see the abstract for all other researchers’ relevant financial disclosures.
Perspective
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Vivek Subbiah, MD
Over the last 50 years, the seminal accomplishment in the world of pediatric oncology has been the application of cytotoxic chemotherapy through cooperative group clinical trials. This has resulted in four out of five children with a diagnosis of cancer being cured of their disease.
Beyond that, further refinements in conventional chemotherapies alone have not rendered dramatic additional benefits for children. Unfortunately, a subgroup of young patients with relapsed/refractory cancers (eg, high-grade brain tumors, advanced bone sarcomas and acute myeloid leukemia) continue to have dismal outcomes. We are in need of novel therapies for these cancers. With hundreds of genomically targeted therapies and immunotherapies in clinical development for adults, we are in an era of unprecedented advances in medical oncology. Many clinical trials of these novel agents rarely include pediatric patients.
To address this, several pediatric-specific precision oncology efforts are underway. In the United States, the NCI-COG Pediatric MATCH (Molecular Analysis for Therapy Choice) — the pediatric counterpart to the adult NCI-MATCH trial — is enrolling patients, as is the ESMART (European Proof-of-Concept Therapeutic Stratification Trial of Molecular Anomalies in Relapsed or Refractory Tumors) trial in Europe.
In this context, INFORM — a registry developed by a consortium of pediatric oncologists and genomics researchers to develop precision medicine-based approaches — has emerged. The findings from this study show that it is possible to identify targets in pediatric cancers that can guide clinical decision-making about treatment options. This registry has opened up the genomic landscape in pediatric oncology and will improve our understanding of clinical impact of targeted therapies for children.
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van Tilburg C, et al. Abstract LBA10503. Presented at: ASCO20 Virtual Scientific Program; May 29-31, 2020.
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