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  • Regardless of the initial treatment most


    Regardless of the initial treatment, most patients with advanced NSCLC experience relapse and disease progression [15]. A subpopulation of immediate concern and clinical need is patients who have advanced NSCLC that is especially aggressive, which is usually defined as disease that rapidly progresses on first-line treatment or disease that is refractory to first-line treatment. These patients have a poor prognosis in the second-line setting. While many antiangiogenic agents, as monotherapy or in combination with chemotherapy, immunotherapy, or targeted TKIs, have been studied in the second-line setting for patients with advanced or metastatic NSCLC, currently, only ramucirumab (independent of histology) or nintedanib (adenocarcinoma histology only) in combination with docetaxel have received FDA and/or EMA approval based on outcomes from large phase 3 studies [8,9]. In addition, post-hoc analyses have been performed in trials to assess outcomes in patients with aggressive NSCLC.
    Safety of antiangiogenic therapies as second-line treatment in patients with aggressive or refractory disease Overall, patients from the REVEL trial who had aggressive or refractory disease had safety profiles that were similar to those in the ITT Asunaprevir with no new safety findings [8,19,20]. Table 1 provides the overall safety data from REVEL patients who had <9 months TSPT (n = 769), PD-BRPT (n = 358), and TTPFL ≤18 weeks (n = 350). The data for TTPFL ≤9 and ≤12 weeks (Supplementary Table A1) were similar to data for TTPFL ≤18 weeks [20]. Patients from the LUME-Lung 1 study who had advanced adenocarcinoma NSCLC and <9 months TSPT (Table 2) had safety overviews similar to the LUME-Lung 1 ITT population with no new safety signals [9,27].
    Patient-reported outcomes of antiangiogenic therapies as second-line treatment in patients with aggressive or refractory disease Quality of life outcomes from subgroups of patients in the REVEL trial who had aggressive or refractory disease were similar to the outcomes from the ITT population (Table 3; Supplementary Table A2) [8,19,20,28]. In the LUME-Lung 1 study, there were no additional detrimental effects on patient self-reported quality of life for adenocarcinoma patients or adenocarcinoma patients with <9 months TSPT in the nintedanib plus docetaxel group versus the placebo plus docetaxel group [9,29].
    Future directions of treatment for second-line NSCLC
    Conclusions Patients with aggressive or refractory NSCLC undoubtedly have an unmet medical need. Clinical trial results suggest that the high-risk population of patients with aggressive, advanced NSCLC may have clinical benefit from second-line treatment with an antiangiogenic therapy added to docetaxel, without additional safety or quality of life concerns. Patients from the REVEL study (regardless of histology) and from the LUME-Lung 1 study (adenocarcinoma histology only) who had aggressive disease or disease that was refractory to first-line therapy had improved outcomes after treatment with an antiangiogenic therapy plus docetaxel, compared with those who received docetaxel alone. There were no additional safety or quality of life concerns observed when either ramucirumab or nintedanib was combined with docetaxel in this high-risk patient population [8,9,19,20,[27], [28], [29]].
    Funding This work was supported by Eli Lilly and Company.
    Conflict of interest statement
    Results and discussion
    Conclusions A new series of synthetic derivatives of XN has been prepared and their effects on angiogenesis have been evaluated in comparison with XN ones. In particular, compounds 4–14 have been tested in vitro on cell proliferation, apoptosis, cell adhesion, migration, invasion and morphogenesis with HUVE cells at 10 μM concentration. Despite the limited number of derivatives synthesized in the present study, some comments about structure-activity relationships (SAR) can be made. The results obtained so far suggest the importance of a phenolic OH group in R3 on A-ring together with a fluorine atom on B-ring for having inhibitory activity on cell migration (see activity of 5 vs 4 and of 13 vs 12, Fig. 4B). The presence of a MOM-protective group in R4 seems to positively influence the ability to block cell proliferation, considering that 8 and 11 are the most potent inhibitors of HUVE cell growth (Fig. 2). Moreover, the introduction of a nitro group in R on B-ring seems to cause toxicity, as shown by the increased apoptosis on HUVECs given by compound 14 already at 10 μM. Noteworthy, the phenolic OH group in R, present in natural XN, does not seem necessary for the antiangiogenic activity. In fact, among all synthesized compounds, the best activity results were exhibited by compound 13, which was the strongest inhibitor of cell adhesion, migration and morphogenesis even compared to XN. This derivative is characterized by a para-methoxy group in R and a fluorine atom in R2 on B-ring. Given the different activity between 13 and its analogue bearing a fluorine in R1, compound 10, the position of F substitution on B-ring seems to be determinant for activity.