Возможности новых антиангиогенных препаратов во второй линии лекарственной терапии немелкоклеточного рака легкого


А.И. Семенова, С.А. Проценко, А.В. Новик, Д.Х. Латипова, Г.М. Телетаева, Т.Ю. Семиглазова

ФГБУ «НИИ онкологии им. Н.Н. Петрова» Минздрава России, Санкт-Петербург
Ведущая роль ангиогенеза в процессах пролиферации и прогрессирования немелкоклеточного рака легкого (НМРЛ) обусловливает повышенный интерес к развитию лекарственных подходов, направленных на подавление этого важнейшего аспекта туморогенеза. Бевацизумаб, продемонстрировавший в комбинации с цитостатиками способность увеличивать выживаемость без прогрессирования и общую выживаемость больных НМРЛ, был первым ингибитором ангиогенеза, одобренным для клинического применения. В настоящее время продолжаются активный поиск и изучение новых лекарственных агентов, подавляющих ангиогенез посредством блокирования различных сигнальных путей. Одним из таких перспективных препаратов является нинтеданиб, представляющий собой мощный тройной ингибитор ангиокиназы, действие которого реализуется в результате блокады не только VEGFR, но и FGFR и PDGFR, участвующих в развитии резистентности опухоли к бевацизумабу. В настоящем обзоре обсуждаются перспективы подобного лекарственного воздействия и анализируются результаты основных клинических исследований III фазы в этой области.

Литература


1. Ferlay J., Soerjomataram I., Ervik M. GLOBOCAN 2012 v1.0, Cancer Incidence and Mortality Worldwide: IARC CancerBase No.11. Lyon: International Agency for Research on Cancer, 2013.

2. World Health Organization: International Agency for Research on Cancer. GLOBOCAN 2012: Estimated cancer incidence, mortality and prevalence worldwide in 2012. Available from: http://globocan.iarc.fr/Pages/fact_sheets_cancer.aspx#. Accessed February 19, 2015.

3. Langer C.J., Besse B., Gualberto A., Brambilla E., Soria J.C. The evolving role of histology in the management of advanced non-small-cell lung cancer. J. Clin. Oncol. 2010;28(36):5311–20.

4. Li T., Kung H.J., Mack P.C., Gandara D.R. Genotyping and genomic profiling of non-small-cell lung cancer: implications for current and future therapies. J. Clin. Oncol. 2013;31(8):1039–49.

5. Ettinger D.S., Akerley W., Borghaei H. Non-small cell lung cancer. J. Natl. Compr. Canc. Netw. 2012;10(10):1236–71.

6. Leighl N.B. Treatment paradigms for patients with metastatic non-small-cell lung cancer: first-, second-, and third-line. Curr. Oncol. 2012;19:S52–58.

7. Reck M., Popat S., Reinmuth N. Metastatic non-small-cell lung cancer (NSCLC): ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up. Ann. Oncol. 2014;25:iii27–39.

8. Scagliotti G.V., Parikh P., Von Pawel J. Phase III study comparing cisplatin plus gemcitabine with cisplatin plus pemetrexed in chemotherapy-naive patients with advanced stage non-small-cell lung cancer. J. Clin. Oncol. 2008;26(21):3543–51.

9. Gridelli C., Ardizzoni A., Ciardiello F., Hanna N., Heymach J.V., Perrone F., Rosell R., Shepherd F.A., Thatcher N., Vansteenkiste J., De Petris L., Di Maio M., De Marinis F. Second-line treatment of advanced non-small cell lung cancer. J. Thorac. Oncol. 2008;3:430–40.

10. Ciuleanu T., Stelmakh L., Cicenas S. Efficacy and safety of erlotinib versus chemotherapy in second-line treatment of patients with advanced, non-small-cell lung cancer with poor prognosis (TITAN): a randomised multicentre, open-label, phase 3 study. Lancet Oncol. 2012;13:300–8.

11. Garassino M.C., Martelli O., Broggini M., Farina G., Veronese S., Rulli E., Bianchi F., Bettini A., Longo F., Moscetti L., Tomirotti M., Marabese M., Ganzinelli M., Lauricella C., Labianca R., Floriani I., Giaccone G., Torri V., Scanni A., Marsoni S. TAILOR trialists. Erlotinib versus docetaxel as second-line treatment of patients with advanced non-small-cell lung cancer and wild-type EGFR tumours (TAILOR): a randomised controlled trial. Lancet Oncol. 2013;14:981–88.

12. Hanna N., Shepherd F.A., Fossella F.V., Pereira J.R., De Marinis F., von Pawel J., Gatzemeier U., Tsao T.C., Pless M., Muller T., Lim H.L., Desch C., Szondy K., Gervais R., Shaharyar., Manegold C., Paul S., Paoletti P., Einhorn L., Bunn P.A. Jr. Randomized phase III trial of pemetrexed versus docetaxel in patients with non-small-cell lung cancer previously treated with chemotherapy. J. Clin. Oncol. 2004;22:1589–97.

13. Shepherd F.A., Dancey J., Ramlau R., Mattson K., Gralla R., O’Rourke M., Levitan N., Gressot L., Vincent M., Burkes R., Coughlin S., Kim Y., Berille J. Prospective randomized trial of docetaxel versus best supportive care in patients with non-small-cell lung cancer previously treated with platinum-based chemotherapy. J. Clin. Oncol. 2000;18:2095–103.

14. Hicklin D.J., Ellis L.M. Role of the vascular endothelial growth factor pathway in tumor growth and angiogenesis. J. Clin. Oncol. 2005;23(5):1011–27.

15. Herbst R.S. Therapeutic options to target angiogenesis in human malignancies. Expert. Opin. Emerg. Drugs. 2006;11(4):635–50.

16. Ellis P.M., Al-Saleh K. Multitargeted anti-angiogenic agents and NSCLC: clinical update and future directions. Crit. Rev. Oncol. Hematol. 2012;84(1):47–58.

17. Leighl N.B. Treatment paradigms for patients with metastatic non-small-cell lung cancer: first-, second-, and third-line. Curr. Oncol. 2012;19:S52–8.

18. Gadgeel S.M. Safety profi le and tolerability of antiangiogenic agents in non-small-cell lung cancer. Clin. Lung Cancer. 2012;13:96–106.

19. Jubb A.M., Harris A.L. Biomarkers to predict the clinical efficacy of bevacizumab in cancer. Lancet Oncol. 2010;11:1172–83.

20. Mok T., Gorbunova V., Juhasz E., Szima B., Burdaeva O., Orlov S., Yu C.J., Archer V., Hilton M., Delmar P., Pallaud C., Reck M. A correlative biomarker analysis of the combination of bevacizumab and carboplatin-based chemotherapy for advanced nonsquamous non-small-cell lung cancer: results of the phase II randomized ABIGAIL study (BO21015). J. Thorac. Oncol. 2014;9:848–55.

21. Garon E.B., Ciuleanu T.E., Arrieta O., Prabhash K., Syrigos K.N., Goksel T., Park K., Gorbunova V., Kowalyszyn R.D., Pikiel J., Czyzewicz G., Orlov S.V., Lewanski C.R., Thomas M., Bidoli P., Dakhil S., Gans S., Kim J.H., Grigorescu A., Karaseva N., Reck M., Cappuzzo F., Alexandris E., Sashegyi A., Yurasov S., Pérol M. Ramucirumab plus docetaxel versus placebo plus docetaxel for second-line treatment of stage IV non-small-cell lung cancer after disease progression on platinum-based therapy (REVEL): a multicentre, double-blind, randomised phase 3 trial. Lancet. 2014;384:665–73.

22. Ganguli A., Wiegand P., Gao X., Carter J.A., Botteman M.F., Ray S. The impact of second-line agents on patients’ health-related quality of life in the treatment for non-small cell lung cancer: a systematic review. Qual. Life Res. 2013;22(5):1015–26.

23. Paz-Ares L.G., Biesma B., Heigener D., von Pawel J., Eisen T., Bennouna J., Zhang L., Liao M., Sun Y., Gans S., Syrigos K., Le Marie E., Gottfried M., Vansteenkiste J., Alberola V., Strauss U.P., Montegriffo E., Ong T.J., Santoro A.; NSCLC

24. Herbst R.S., Sun Y., Eberhardt W.E. Vandetanib plus docetaxel versus docetaxel as second-line treatment for patients with advanced non-small-cell lung cancer (ZODIAC): a double-blind, randomised, phase 3 trial. Lancet Oncol. 2010;11:619–26.

25. Natale R.B., Thongprasert S., Greco F.A. Phase III trial of vandetanib compared with erlotinib in patients with previously treated advanced non-small-cell lung cancer. J. Clin. Oncol. 2011;29:1059–66.

26. Gori B., Ricciardi S., Fulvi A., Intagliata S., Del Signore E., de Marinis F. New antiangiogenics in non-small cell lung cancer treatment: VargatefТМ (BIBF 1120) and beyond. Ther. Clin. Risk Manag. 2011;7:429-40

27. Hilberg F., Roth G.J., Krssak M., Kautschitsch S., Sommergruber W., Tontsch-Grunt U., Garin-Chesa P., Bader G., Zoephel A., Quant J., Heckel A., Rettig W.J. BIBF 1120: triple angiokinase inhibitor with sustained receptor blockade and good antitumor efficacy. Cancer Res. 2008;68:4774–82.

28. Hilberg F., Brandstetter I. Efficacy of BIBF 1120, a potent triple angiokinase inhibitor, in models of human non-small cell lung cancer is augmented by chemotherapy. Eur. J. Cancer. 2007;2:S380.

29. Stopfer P., Rathgen K., Bischoff D., Lüdtke S., Marzin K., Kaiser R., Wagner K., Ebner T. Pharmacokinetics and metabolism of BIBF 1120 after oral dosing to healthy male volunteers. Xenobiotica. 2011;41:297–311.

30. Okamoto I., Kaneda H., Satoh T., Okamoto W., Miyazaki M., Morinaga R., Ueda S., Terashima M., Tsuya A., Sarashina A., Konishi K., Arao T., Nishio K., Kaiser R., Nakagawa K. Phase I safety, pharmacokinetic, and biomarker study of BIBF 1120, an oral triple tyrosine kinase inhibitor in patients with advanced solid tumors. Mol. Cancer Ther. 2010;9:2825–33.

31. Doebele R.C., Conkling P., Traynor A.M., Otterson G.A., Zhao Y., Wind S., Stopfer P., Kaiser R., Camidge D.R. A phase I, open-label dose-escalation study of continuous treatment with BIBF 1120 in combination with paclitaxel and carboplatin as first-line treatment in patients with advanced non-small-cell lung cancer. Ann. Oncol. 2012;23:2094–102.

32. Reck M., Kaiser R., Eschbach C., Stefanic M., Love J., Gatzemeier U., Stopfer P., von Pawel J. A phase II double-blind study to investigate efficacy and safety of two doses of the triple angiokinase inhibitor BIBF 1120 in patients with relapsed advanced non-small-cell lung cancer. Ann. Oncol. 2011;22:1374–81.

33. Reck M., Mellemgaard A. Emerging treatments and combinations in the management of NSCLC: clinical potential of nintedanib. Biologics. 2015;9:47–56.

34. Reck M., Kaiser R., Mellemgaard A., Douillard J.Y., Orlov S., Krzakowski M., von Pawel J., Gottfried M., Bondarenko I., Liao M., Gann C.N., Barrueco J., Gaschler-Markefski B., Novello S.; LUME-Lung 1 Study Group. Docetaxel plus nintedanib versus docetaxel plus placebo in patients with previously treated non-small-cell lung cancer (LUME-Lung 1): a phase 3, double-blind, randomised controlled trial. Lancet Oncol. 2014;15(2):143–55.

35. Novello S., Kaiser R., Mellemgaard A., Douillard J.Y., Orlov S., Krzakowski M., von Pawel J., Gottfried M., Bondarenko I., Liao M., Barrueco J., Gaschler-Markefski B., Griebsch I., Palmer M., Reck M; LUME-Lung 1 Study Group. Analysis of patient-reported outcomes from the LUME-Lung 1 trial: a randomized, double-blind, placebo-controlled, Phase III study of second-line nintedanib in patients with advanced non-small cell lung cancer. Eur. J. Cancer. 2015;51:317–26.

36. Hocke J., Glomb P., Kaiser R., Barrueco J., Gaschler-Markefski B. Retrospective evaluation of the futility analysis in LUME-Lung 2, a phase III trial of nintedanib (BIBF 1120) plus pemetrexed for second line NSCLC patients. Presented at the International Society for Clinical Biostatistics 35th Annual Meeting, Vienna, Austria, August 24–28, 2014.

37. Popat S., Mellemgaard A., Fahrbach K., Martin A., Rizzo M., Kaiser P., Griebsch I., Reck M. Nintedanib plus docetaxel as second-line therapy in patients with non-small-cell lung cancer: a network meta-analysis. Future Oncol. 2015;11:409–20.

38. Hilberg F., Haslinger C., Garin-Chesa P., Adolf G.R. Molecular correlates of clinical benefit from antiangiogenic therapy for patients with lung adenocarcinoma: a hypothesis. J. Clin. Oncol. 2014;32 Suppl:Abstr. e22080.

39. Roth G.J., Binder R., Colbatzky F., Dallinger C., Schlenker-Herceg R., Hilberg F., Wollin S.L., Kaiser R. Nintedanib: from discovery to the clinic. J. Med. Chem. 2015;58:1053–63.

40. Recka M., Mellemgaard A., von Pawel J., Gottfried M., Bondarenko I., Cheng Y., Zarogoulidis K., Luft A., Bennouna J., Barrueco J., Aboshady H., Hocke J., Kaiser R., Douillard J.-Y., for the LUME-Lung 1 Study. Anti-angiogenic-specific adverse events in patients with non-smallcell lung cancer treated with nintedanib and docetaxel. Lung Cancer. 2015;90:267–73.


Об авторах / Для корреспонденции


А.И. Семенова – к.м.н., с.н.с. научного отдела инновационных методов терапевтической онкологии и реабилитации, врач-онколог отделения химиотерапии и инновационных технологий ФГБУ «НИИ онкологии им. Н.Н. Петрова» Минздрава России, Санкт-Петербург; e-mail: mirannia@yandex.ru


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