Background: The Network Genomic Medicine (NGM) Lung Cancer is a health care provider network offering comprehensive next generation sequencing (NGS)-based multiplex genotyping on a central diagnostics platform in Cologne for inoperable lung cancer patients (pts) in Germany. Methods: The NGS panel used consists of 14 genes and 102 amplicons to cover potentially targetable aberrations. Mutation analyses were run on an Illumina (MySeq) platform, FISH analyses were performed separately. In 2015, we have started the second outcome evaluation for all NGM pts who had received NGS-based molecular diagnostics. In particular, we have focused on pts with activating EGFR mutation (EGFR+), ALK translocation (ALK+), BRAF-V600E mutation (BRAF+), HER2 amplification (HER2+) and ROS1 translocation (ROS1+) and on the outcome of pts treated in clinical trials (ct). Results: From 2013-2015 6210 lung cancer pts (n = 4244 non-squamous NSCLC) were genotyped. Overall survival (OS) is shown for 934 NSCLC pts including 110 pts treated in ct. For 108 EGFR+ pts, the OS of pts treated in ct with different 3^rd generation EGFR-TKIs was 55 months (n = 25) vs 22 months in the control group (n = 83) (p = 0,002; mean OS: 29 months; 95%CI: 36-83 months). For 85 ALK+ pts, the OS of pts treated in ct with next-generation ALK-inhibitor after crizotinib failure was 35 months (n = 19) compared to OS of 23 months for 45 pts treated with crizotinib only and 8 months for 19 pts treated with no ALK inhibitors (p < 0,0001; mean OS: 22 months; 95%CI: 22-33 months). For 32 BRAF+ pts and 11 HER2+ pts, the mean OS was 23 months (95%CI: 12-26 months) and 25 months (95%CI: 15-34 months) (p = 0,022). The mean OS of 13 ROS1+ pts was not reached (95%CI: 58-100 months). Conclusions: Here we show successful implementation of NGS-based molecular diagnostics in clinical routine use. Moreover, molecular diagnostics triggers personalized therapy in – and outside clinical trials and improves survival for EGFR+, ALK+, ROS1+, BRAF+ and HER2+ pts. In particular, the use of next-gen. inhibitors after failure of first gen. inhibitors in EGFR+ and ALK+ pts leads to a significant and substantial additional survival benefit.