Abstract SY09-01: A comprehensive European approach to precision pediatric cancer medicine

Cure rates for pediatric malignancies have stagnated at around 80% for two decades. A “more of the same” approach will likely not help a considerable proportion of the remaining ~20% of children who cannot be cured to date, thus implying an urgent need for innovative treatment strategies. The aim of the INFORM (INdividualized Therapy FOr Relapsed Malignancies in Childhood) program is to translate next generation molecular diagnostics into a personalized, biomarker-driven treatment strategy. The program consists of two major pillars: the INFORM registry providing a molecular screening platform and the INFORM2 series of exploratory biomarker-driven phase I/II trials, conducted through the European Innovative Therapies for Children with Cancer (ITCC) network. This is complemented by an international public-private preclinical testing platform, ITCC-P4, which aims at systematic and rigorous preclinical filtering of novel assets for a potential indication in the pediatric space. INFORM is a multi-national registry, open across nine European countries, offering comprehensive real-time molecular profiling for pediatric patients with no standard treatment options. INFORM is complemented by corresponding programs in France, the Netherlands, the UK and Denmark to cover most of the European population. To date, more than 1,100 patients have been registered and profiled through INFORM, using whole-exome and low-coverage whole genome sequencing, as well as RNA transcriptome sequencing and DNA methylation analysis. In 2019 alone, almost 400 patients were recruited. A comprehensive analysis of the first ~800 patients enrolled including a thorough primary-relapse study to investigate intra-individual tumor evolution is currently ongoing and first results will be presented. Potentially actionable targets of ‘moderate9 or higher priority (which are reported in the weekly interdisciplinary molecular tumor board and documented in the online database) were identified in approximately half of all patients, with many having been treated with mechanism-of-action based therapies on the basis of the generated data. Recently we have also added real-time drug profiling on short-term tumor cell cultures as an additional screening tool in the context of the COMPASS Consortium. The long-term goals of this program are 1) to inform a series of early-phase, cross-entity, combination clinical trials to improve access to innovative treatment approaches for pediatric patients (e.g., INFORM2 trial series); and 2) to deliver evidence demonstrating that the molecular profiling is of clinical value to patients, in the assumption that these costs will be reimbursed by health insurances as part of routine standard-of-care for high-risk pediatric cancer patients. Within the preclinical platform ITCC-P4, consortium members have established and molecularly characterized more than 150 patient-derived xenograft models from pediatric solid tumors (target: 400 models). These are now being utilized for systematic single-mouse preclinical trials applying both standard-of-care treatments as well as innovative new drugs from the portfolios of participating companies in selected pediatric cancer (sub)-entities through standardized Mechanism-of-Action-based matching with pediatric tumor biology. Applying a uniform and comprehensive interdisciplinary strategy for molecular diagnostic, preclinical and early clinical activities in Europe, we hope to be able to tackle the challenge of pediatric very high-risk diseases in a more effective way. Citation Format: Stefan M. Pfister, David TW Jones, Barbara C. Jones, Balasubramanian Gnana Prakash, Mirjam Blattner-Johnson, Elke Pfaff, Cornelis M. Van Tilburg, Sina Oppermann, Louis Stancato, Hubert Caron, Gilles Vassal, Kristian Pajtler, Natalie Jager, Olaf Witt. A comprehensive European approach to precision pediatric cancer medicine [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr SY09-01.