Cancer stage at diagnosis determines treatment options and has a strong influence on the length of survival. In the SEER database ( 39), 57% of patients are diagnosed with advanced stage (metastatic) disease, with a 5y - overall survival (OS) of 4.2%. For the overall population 5y OS is 17.4%. Lung cancer is diagnosed at a median age of 70 years. Non-small -cell lung cancers (NSCLC) account for 85% –90% of lung cancers, while small -cell lung cancer (SCLC) has been decreasing in frequency in many countries over the last two decades ( 39). Tumor subtypes are considered in therapeutic decisions. Adenocarcinoma is the most common histologic subtype. Approximately 63% of advanced NS CLC are diagnosed as adenocarcinoma, 17% as squamous, and 20% as not otherwise specified ( 37). Platinum -based doublet chemotherapy is the standard first-line treatment for non -selected patients with advanced NSCLC who have a good performance status. Platinum -based doublet chemotherapy prolongs survival and improves quality of life (QoL) in patients with PS 0 –2. For most patients, four cycles of chem otherapy are recommended, notably when maintenance treatment is considered, with a maximum of six cycles. Several regimens of first -line treatment have shown comparable efficacy. Cisplatin compared to carboplatin globally has reported better response rate (RR) and in the subgroup of patients with non -squamous histology when cisplatin is added to third -generation regimens has reported better OS. There is no single platinum -based doublet standard chemotherapy. Pemetrexed use should be restricted to non -squamo us NSCLC and bevacizumab combined with paclitaxel –carboplatin regimen improves OS in patients with non-squamous histology and PS 0 – 1, and may be offered after exclusion of contraindications (65). Personalized treatment has changed the diagnostic and treatment approach in NSCLC and could have an impact on patients’ outcome ( 44) as 30% of advanced NSCLC have some kind of actionable oncogenic driver mutation. T he most common are sensitizing EGFR mutation ( around 17% in no n-Asian population), ALK-rearrangements (8%) and others such as ROS1 - rearrangements. These oncogenic drivers are almost always mutually exclusive in patients with NSCLC. Targeted agents currently approved for the treatment of NSCLC and include the first - generation, reversible EGFR -targeted tyrosine -kinase inhibitors (TKIs) erlotinib and gefitinib; the second -generation irreversible EGFR -TKI, afatinib; and the ALK inhibitor, crizotinib. New treatments indicated for acquired resistance are being tested. Erlotinib, docetaxel and pemetrexed are approved second -line therapies for advanced NSCLC patients who progress after first -line treatment ( 65). The OS for these second line therapies ranged from 5.5 to 8.3 for chemoth erapy and 5.3 to 6.7 for erlotinib ( 15, 24, 34, 73). Some differences exist amon g these therapies. Pemetrexed has shown a similar efficacy to docetaxel in OSE2101 Protocol OSE2101C301 Confidential Version n°6.0 Page 27 of 101 02 February 2022 second -line setting but with a significantly better toxicity profile ( 34). Efficacy of pemetrexed compared to docetaxel according to histology has been reviewed ( 71) and this favored pemetrexed specifically in large cell carcinoma, alth ough this histologic category has been revised subsequently ( 77). The TITAN trial reported that erlotinib was equivalent to pemetrexed or docetaxel in refractory patients (progression during first -line chemotherapy) unselected for EGFR status ( 15). In molecularly selected wild -type (wt) EGFR popul ation, the TAILOR trial showed that docetaxel was superior to erlotinib as second -line therapy with respect to OS and progression free survival (PFS) ( 24). However, in the subset analysis of EGFR -wt tumors, the DELTA trial failed to demonstrate a gain in OS for docetaxel vs. erlotinib ( 42), rei nforcing erlotinib as a potential second -line treatment option independently of EGFR status. Currently, the efficacy of approved drugs for second -line treatment in NSCLC or their response rate are limited and new treatment options are awaited. Tumor ang iogenesis is critical for tumor progression. Recently two randomized Phase III trials have tested the efficacy of antiangiogenic therapies in second -line for advanced NSCLC. The LUME -lung 1 trial ( 64) was conducted in 1314 patients and demonstrated that docetaxel plus a multi -antiangiogenic (VEGFR, PDGFR, FGFR) angiokinase inhibitor, nintedanib, improved PFS, the primary endpoint of the trial (3.4 mo . Vs.