The pediatric precision oncology study INFORM: Clinical outcome and benefit for molecular subgroups.

Abstract

LBA10503 Background: Several pediatric precision oncology programs have identified molecular actionable variants. However, the clinical benefit is largely unknown. We here report a target prioritization algorithm and associated clinical outcome. Methods: INFORM is a prospective, non-interventional, multi-center, multi-national, and feasibility registry collecting clinical and molecular data. Patients with refractory/relapsed/progressive malignant disease, including primary diagnosis high-risk entities, can be enrolled. Fresh frozen tumor material (incl. germline DNA) was subjected to WES, lcWGS, RNA-Seq, RNA expression array and DNA-methylation. A weekly interdisciplinary molecular board reviewed and prioritized alterations based on a 7- step scale from ‘very high’ to ‘very low’, depending on the type of alteration and its entity specific relevance (described by Worst et al. Eur J Cancer 2016). Results: To date, more than 1300 patients were enrolled. 525 patients finished follow-up and were included in this analysis. They were enrolled in 72 centers in 8 countries. The median age was 12.0 (range 0 - 40) years. Average turnaround time from submission to report was 25.4 days. Median PFS and OS were 116 (95% CI 105 – 135) and 289 (95% CI 250 – 335) days. The distribution of the highest priority target per patient was: very high 8.0%, high 14.8%, moderate 20.3%, intermediate 23.6%, borderline 14.4%, low 2.5%, very low 1.0% and no actionable target 15.4%. 149 patients received targeted treatment on the basis of identified targets, of which 20 had a very high priority target (mostly ALK, BRAF and NRAS mutations and MET and NTRK-fusions) with a median PFS of 204.5 (95% CI 91.0 – 628.0) compared to 114 (95% CI 103 – 133) days in all other 505 patients (p = 0.0095). OS did not show clinically relevant differences. Explorative analysis of the time to progression (TTP) ratio (before compared to after enrollment) showed that patients treated according to a very high priority target had a higher TTP ratio (1.0) compared to all other patients (0.7). Possible predisposition syndromes were identified in 7.8% of patients, half of which were newly diagnosed. Methylation analysis provided a diagnosis refinement in 8% of CNS tumors. Conclusions: Pediatric precision oncology in a real world, multi-national setting is feasible. The prioritization algorithm identifies subgroups benefitting from molecularly matched targeted treatment. Still, for the patients without a very high priority target further layers of molecular and functional data should be incorporated in future programs.

Diagnosis and therapy of tumors with NTRK gene fusion

“…Die INFORM-Plattform bietet für Hochrisikoerkrankungen im Rezidivfall, aber auch für bestimmte Hochrisikoerkrankungen im Rahmen der Primärdiagnose (z. B. metastasierte Rhabdomyosarkome und hochmaligne Gliome [HGG]) umfassende molekulare Analysen an (WES, lcWGS, RNAseq und DNA-Methylierung) [ 63 ]. Für niedrigmaligne Gliome (LGG) steht bundesweit die LOGGIC-Core-Plattform zur Verfügung, die eine panelbasierte NGS-Analytik und eine RNA-Sequenzierung in Fällen anbietet, bei denen die Treiberalteration mittels Panel nicht identifiziert wurde [ 30 , 40 , 41 , 58 ].…”

Precision Medicine in Osteosarcoma: MATCH Trial and Beyond

“…The translation of genomic findings into clinical oncology continues to grow rapidly, offering novel promising choices of therapy for children and adults with cancer. For those patients presenting druggable genomic alterations these targeted treatments could significantly improve their life span and quality [ 18 ].…”

“…In this light, Worst and colleagues developed a work-flow able to rank genomic alterations in seven levels of increasing clinical relevance (e.g., from “very high” to “very low”) on the basis of their effect on the encoded protein, the availability of a direct targeting drug, and literature evidences of possible pathway activation [ 17 ]. In the INFORM pilot study, patients with a very high priority target alterations (e.g., ALK, BRAF, and NRAS mutations, and MET and NTRK-fusions) showed an improvement in the Progression-Free Survival (PFS) [ 18 ]. Indeed, the median PFS in paediatric patients with a high priority genomic alteration treated with the matched drug was significantly higher compared to that of all patients with no druggable aberration (i.e., 204.5 and 114 days, respectively— p = 0.0095) [ 18 ].…”

“…In the INFORM pilot study, patients with a very high priority target alterations (e.g., ALK, BRAF, and NRAS mutations, and MET and NTRK-fusions) showed an improvement in the Progression-Free Survival (PFS) [ 18 ]. Indeed, the median PFS in paediatric patients with a high priority genomic alteration treated with the matched drug was significantly higher compared to that of all patients with no druggable aberration (i.e., 204.5 and 114 days, respectively— p = 0.0095) [ 18 ]. Hence, a promptly identification of patients whose tumours are harbouring a high priority target genomic alteration is necessary to better address the physician’s treatment choice.…”

Recent progress in the treatment of cancer in children

“…[149][150][151] However, the fraction of patients with solid tumors for which there is strong clinical evidence to support the benefit of such therapy is <5% in most studies. 149,150,152 To address this limitation, multiple ongoing clinical trials are studying the benefit of therapy matched to molecular alterations in a histology-agnostic fashion. Recent FDA approvals of both checkpoint inhibitors and molecularly targeted therapy for the treatment of pediatric cancer in a histology-agnostic fashion highlight the promise of this approach.…”