Data from Upfront Biology-Guided Therapy in Diffuse Intrinsic Pontine Glioma: Therapeutic, Molecular, and Biomarker Outcomes from PNOC003

Abstract

<div>AbstractPurpose:<p>PNOC003 is a multicenter precision medicine trial for children and young adults with newly diagnosed diffuse intrinsic pontine glioma (DIPG).</p>Patients and Methods:<p>Patients (3–25 years) were enrolled on the basis of imaging consistent with DIPG. Biopsy tissue was collected for whole-exome and mRNA sequencing. After radiotherapy (RT), patients were assigned up to four FDA-approved drugs based on molecular tumor board recommendations. H3K27M-mutant circulating tumor DNA (ctDNA) was longitudinally measured. Tumor tissue and matched primary cell lines were characterized using whole-genome sequencing and DNA methylation profiling. When applicable, results were verified in an independent cohort from the Children's Brain Tumor Network (CBTN).</p>Results:<p>Of 38 patients enrolled, 28 patients (median 6 years, 10 females) were reviewed by the molecular tumor board. Of those, 19 followed treatment recommendations. Median overall survival (OS) was 13.1 months [95% confidence interval (CI), 11.2–18.4] with no difference between patients who followed recommendations and those who did not. H3K27M-mutant ctDNA was detected at baseline in 60% of cases tested and associated with response to RT and survival. Eleven cell lines were established, showing 100% fidelity of key somatic driver gene alterations in the primary tumor. In H3K27-altered DIPGs, <i>TP53</i> mutations were associated with worse OS (<i>TP53</i><sub>mut</sub> 11.1 mo; 95% CI, 8.7–14; <i>TP53</i><sub>wt</sub> 13.3 mo; 95% CI, 11.8–NA; <i>P</i> = 3.4e−2), genome instability (<i>P</i> = 3.1e−3), and RT resistance (<i>P</i> = 6.4e−4). The CBTN cohort confirmed an association between <i>TP53</i> mutation status, genome instability, and clinical outcome.</p>Conclusions:<p>Upfront treatment-naïve biopsy provides insight into clinically relevant molecular alterations and prognostic biomarkers for H3K27-altered DIPGs.</p></div>