2.7 mo., HR 0.79, 95%CI 0.68 -0.79, p=0.0019). Although an OS benefit was not noted in the study population (10.1 mo. Vs. 9.1 mo., HR 0.94, 95%CI 0.83 -1.05, p=0.27), in the hierarchical analysis, nintedanib plus docetaxel significantly improved OS in the subgroup of adenocarcinomas (12.6 mo. Vs. 10.3 mo., HR 0.83, 95%CI 0.7 -0.99, p=0.0359), as well as in those adenocarcinoma tumors with a more aggressive behavior (defined progression within 9 months of starting prior first -line therapy; 10.9 mo. Vs. 7.9 mo., HR 0.75, 95%CI 0.6 -0.92, p=0.0073). Toxicity grade 3 or higher was more common in combination arm than monotherapy (31.3% vs. 26.7%, mainly diarrhea, and reversible increase in transaminases) ( 64), however, it did not have an impact on patient self -reported QoL ( 56). The OS benefit with nintedanib and docetaxel may have been optimized by the fact that the population included in the trial was highly selected (the study excluded patients with brain metastasis or radiological evidence of blood vessel involvement or cavitation or with hemopt ysis or thrombosis; and median age was only 60) . These results have led to the approval of nintedanib in Europe, not in the US (as of April 2015) as second -line treatment in combination with docetaxel in locally advanced or metastatic NSCLC patients. Another product, ramucirumab, a monoclonal antibody anti VEGFR -2 was tested in the REVEL trial ( 25, 61). A total of 1253 patients were included in this Phase III study and the addition of ramucirumab, to standard therapy with docetaxel improved OS, the primary endpoint of the trial, (10.5 mo. Vs.