The nNGM Preclinical Platform: Preclinical research to generate evidence for patients with non-small cell lung cancer and variants of unknown significance

The national network genomic medicine lung cancer (nNGM) improves patient care of non-small cell lung cancer (NSCLC) patients by applying harmonized state-of-the-art molecular testing. Patients with actionable alterations can benefit from targeted molecular therapy options. However, systematic molecular testing frequently also leads to the discovery of mutations with no clear clinical actionability, commonly classified as variants of unknown significance (VUS). Since individual VUS are often rare, generation of evidence from clinical trials is difficult. The preclinical platform of the nNGM aims to provide functional data on VUS by combining preclinical research efforts with clinical data available from the nNGM network, thereby generating evidence for patients with VUS. Clinicians can contact the preclinical platform with characterization requests for VUS. An expert team compiles literature data, clones the mutations into in vitro model systems, and conducts functional testing for oncogenicity and resistance mechanisms. Results are recorded in the MURIPEDIA knowledge data base, and correlation of predicted treatment sensitivity and clinical response informs a self-learning, evidence-generating system. The service is integrated with individual and collaborative research activities of the contributing groups for the systematic generation of preclinical evidence and includes computational methods for driver detection, and the setup of organoid biobanks as the groundwork for future patient-derived in vitro models. A total of 32 on-demand requests have been processed by scientists from the preclinical platform. Specialized in vitro testing with a turnaround time of 6 – 12 weeks is available for VUS occurring in EGFR, FGFR1, FGFR2, FGFR3, FGFR4, ROS1, or BRAF. From 19 requests concerning VUS of EGFR with no prior available data, 6 novel EGFR in vitro drivers were identified and profiled. The nNGM preclinical platform offers a comprehensive on-demand characterization service for VUS in NSCLC patients supporting the concept of knowledge-generating patient care in the nNGM.