Background: Targeted therapies (TT) are approved in NSCLC based on a limited number of oncogenic drivers. Numerous additional TT can be matched to other molecular alterations found in comprehensive profiles. We investigated the effect of 8 TT compared to SoC as a maintenance strategy after chemotherapy in pts with metastatic NSCLC. Methods: In SAFIR02-LUNG trial (NCT: 02117167), open-label multicentric phase II randomized trials, PS 0-1 pts with ALK/EGFR WT NSCLC after a CR/PR/SD to 4 cycles of platinum-based chemotherapy were selected. All pts underwent a fresh biopsy, followed by targeted sequencing on 70 genes and SNP-array when > 30% cancer cells were present on HES slides. In case of genomic alteration (including KRAS, ERBB2, BRAF, BRCA mutations), pts were randomized 2:1 between 8 TT and SoC. TT allocation was decided during weekly national tumor board, based on predefined guidelines. The primary endpoint was Progression-Free Survival (PFS) and the secondary endpoint was Overall Survival (OS). Results: 999 patients were enrolled and 394 had a molecular alteration eligible for the study. Among the 175 randomized pts (between July 2014 and May 2019), 116 received TT (65 selumetinib, 18 vistusertib, 9 capivasertib, 8 AZD4547, 5 AZD8931, 5 vandetanib, 4 olaparib, 1 savolitinib) and 59 SoC (54 pemetrexed, 4 gemcitabine and 1 erlotinib). Median age was 60, 40.6% were female, 4.6% never-smoker, 44% were PS 0, 88.6% had a non-squamous NSCLC and 26.9% a PR to chemotherapy. At data cut-off, 168 pts had progressed or died. With a median follow-up of 42.0 months (mo), median PFS was 2.7 mo (95% confidence interval (CI) 1.6 to 2.7) with TT vs. 2.7 mo (95%CI 1.6-4.1) with SoC (HR for disease progression or death 1.00; 95%CI = 0.73 to 1.38; p = 0.978). There was no significant PFS differences among the molecular subgroups; in the cohort with KRAS or BRAF mutation without STK11 mutations the HR for disease progression or death was 0.76; 95%CI = 0.52 to 1.13; p = 0.17. Median OS was 14.3 mo (95%CI 11.0-18.3) with TT vs. 14.1 mo (95% CI 8.0-30.9) with SoC (HR for death 1.12; 95%CI = 0.75-1.65; p = 0.581). Grade 3 or 4 treatment-related adverse events occurred in 31 pts (26.7%) on TT (G3: 30 pts (25.9%), G4: 1 pt (0.8%)) and in 13 (22%) on SoC (G3 8 pts, G4 5 pts). Conclusions: The SAFIR02-LUNG trial demonstrated the feasibility of a routine precision medicine for advanced NSCLC. However, the monotherapy TT used as maintenance therapy after platinum-based chemotherapy failed to improve PFS or OS in this advanced ALK/EGFR WT NSCLC pts population. Newly available therapeutic options (ex. for KRASG12C, RET, NTRK, ERBB2, NRG1, etc) need to be evaluated. Clinical trial information: 2013-001653-27.