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Background: Nintedanib(N)inhibits VEGFRs,PDGFRs,and FGFRs.LUME Lung 1 is a placebo(P)controlled phase Ⅲ trial of N + docetaxel(D)in patients(pts)with locally advanced/metastatic NSCLC progressing after first-line therapy.Methods: Stage ⅢB/Ⅳ or recurrent NSCLC pts(stratified by histology,ECOG PS,prior bevacizumab,and brain metastases)were randomized to N 200 mg bid + D 75 mg/m2 q21d(n=655)or P + D(n=659).1° endpoint was centrally reviewed PFS after 713 events(2 sided stratified log-rank,α=5%,β=10%).Key 2° endpoint of OS was analyzed hierarchically after 1,121 events(2 sided,adjusted α=4.98%,β=20%),first in adenocarcinoma(adeno)pts <9 mo since start of first-line therapy(T<9mo; identified as a prognostic/predictive biomarker [ASCO 13]),followed by all adeno pts and then all pts.Predefined sensitivity analyses added sum of longest diameters of target lesions(SLD)to stratification factors in the Cox model.Results: Pt characteristics were balanced between the arms.N + D significantly prolonged PFS vs P + D(HR 0.79; CI: 0.68,0.92; p=0.0019; median 3.4 vs 2.7 mo)regardless of histology(squamous HR 0.77,p=0.02; adeno HR 0.77,p=0.02).OS was significantly prolonged in all adeno pts(HR 0.83; p=0.0359; median 12.6 vs 10.3 mo)with the greatest improvement seen in T<9mo adeno pts(HR 0.75; p=0.0073; median 10.9 vs 7.9 mo).A trend for improved OS was seen in all pts(HR 0.94; p=0.272; median 10.1 vs 9.1).When adjusted for SLD,a significant OS benefit was seen in all pts(HR 0.88; CI: 0.78,0.99; p=0.0365).Disease control rates were significantly improved with N + D in all adeno pts(odds ratio [OR] 1.93; p<0.0001),T<9mo adeno pts(OR 2.90; p<0.0001)and all pts(OR 1.68; p<0.0001).The most common AEs were diarrhea(any: 42.3 vs 21.8%; Gr ≥3: 6.6 vs 2.6%)and ALT elevations(any: 28.5 vs 8.4%; Gr ≥3: 7.8 vs 0.9%).Incidence of CTCAE Gr ≥3 AEs was 71.3 vs 64.3%.Withdrawals due to AEs(22.7 vs 21.7%)were similar in both arms,as were Gr ≥3 hypertension,bleeding or thrombosis.Conclusions: N + D significantly improved PFS independent of histology,and prolonged OS for adeno pts.AEs were generally manageable with dose reductions and symptomatic treatment.