Ингибиторы тирозинкиназ в лечении распространенного рака легкого на примере системы льготного лекарственного обеспечения города Москвы

Рак легкого (РЛ) является наиболее частой причиной смерти от онкологических заболеваний. Терапия РЛ остается на сегодняшний день серьезной проблемой онкологии. Широкое распространение в практической онкологии получают таргетные препараты, включающие ингибиторы тирозинкиназ (ИТК), которые применяются при лечении распространенного немелкоклеточного РЛ. Работа выполнена в рамках задачи, поставленной Департаментом здравоохранения города Москвы (ДЗМ) по совершенствованию механизмов финансового расходования средств ДЗМ с целью улучшения льготного лекарственного обеспечения москвичей. Обзор посвящен клиническим аспектам применения тирозинкназных ингибиторов. В статье обобщены результаты ключевых клинических исследований эффективности ИТК, представлен анализ потребления этих препаратов в системе льготного лекарственного обеспечения жителей Москвы, обсуждаются перспективы дальнейшего развития таргетной терапии в лечении РЛ. Наиболее востребованными в системе льготного лекарственного обеспечения москвичей в 2018 г. оказались такие таргетные препараты, как гефитиниб, эрлотиниб и афатиниб. Выбор таргетных препаратов напрямую зависит от молекулярно-генетического типа опухоли. В целях дальнейшего совершенствования расходования финансовых ресурсов, в т. ч. ДЗМ, важно установить молекулярный профиль опухоли у пациента и назначить наиболее эффективные ИТК в каждом конкретном случае.

1. Amanam I., Gupta R., Mambetsariev I., Salgia R. The brigatinib experience: a new generation of therapy for ALKpositive non-small-cell lung cancer. Future Oncol. 2018; 14 (19): 1897–1908. DOI: 10.2217/fon-2017-0545.

2. Каприн А.Д., Старинский В.В., Петрова Г.В., ред. Злокачественные новообразования в России в 2016 году (заболеваемость и смертность). М.: МНИОИ им. П.А.Герцена – филиал ФГБУ «НМИЦ радиологии» Минздрава России; 2018. Доступно на: https://oncologyassociation.ru/files/medstat/2016.pdf

3. Zugazagoitia J., Molina-Pinelo S., Lopez-Rios F., PazAres L. Biological therapies in nonsmall cell lung cancer. Eur. Respir. J. 2017; 49 (3): 1601520. DOI: 10.1183/13993003.01520-2016.

4. Wang Y., Hu G.F., Wang Z.H. The status of immunosuppression in patients with stage IIIB or IV non-small-cell lung cancer correlates with the clinical characteristics and response to chemotherapy. Onco Targets Ther. 2017; 10: 3557–3566. DOI: 10.2147/OTT.S136259.

5. Gadgeel S.M. Personalized therapy of non-small cell lung cancer (NSCLC). Adv. Exp. Med. Biol. 2016; 890: 203–222. DOI: 10.1007/978-3-319-24932-2_11.

6. Chan B.A., Hughes B.G.M. Targeted therapy for non-small cell lung cancer: current standards and the promise of the future. Transl. Lung Cancer Res. 2015; 4 (1): 36–54. DOI: 10.3978/j.issn.2218-6751.2014.05.01.

7. Alamgeer M., Ganju V., Watkins D.N. Novel therapeutic targets in non-small cell lung cancer. Curr. Opin. Pharmacol. 2013; 13 (3): 394–401. DOI: 10.1016/j.coph.2013.03.010.

8. Savas P., Hughes B., Solomon B. Targeted therapy in lung cancer: IPASS and beyond, keeping abreast of the explosion of targeted therapies for lung cancer. J. Thorac. Dis. 2013; 5 (Suppl. 5): S579–592. DOI: 10.3978/j.issn.2072-1439.2013.08.52.

9. Keedy V.L., Temin S., Somerfield M.R. et al. American Society of Clinical Oncology provisional clinical opinion: epidermal growth factor receptor (EGFR) Mutation testing for patients with advanced non-small-cell lung cancer considering first-line EGFR tyrosine kinase inhibitor therapy. J. Clin. Oncol. 2011; 29 (15): 2121–2127. DOI: 10.1200/JCO.2010.31.8923.

10. Califano R., Greystoke A., Lal R. et al. Management of ceritinib therapy and adverse events in patients with ALKrearranged non-small cell lung cancer. Lung Cancer. 2017; 111: 51–58. DOI: 10.1016/j.lungcan.2017.06.004.

11. Weart T.C., Miller K.D., Simone C.B. Spotlight on dabra - fenib/trametinib in the treatment of non-small-cell lung cancer: place in therapy. Cancer Manag. Res. 2018; 10: 647– 652. DOI: 10.2147/CMAR.S142269.

12. Nivolumab approved for lung cancer. Cancer Discov. 2015; 5 (5): OF 1. DOI: 10.1158/2159-8290.CD-NB2015-042.

13. Ranson M., Hammond L.A., Ferry D. et al. ZD1839, a selec tive oral epidermal growth factor receptor-tyrosine kinase inhibitor, is well tolerated and active in patients with solid, malignant tumors: results of a phase I trial. J. Clin. Oncol. 2002; 20 (9): 2240–2250. DOI: 10.1200/JCO.2002.10.112.

14. Ho C., Murray N., Laskin J. et al. Asian ethnicity and adenocarcinoma histology continues to predict response to gefitinib in patients treated for advanced non-small cell carcinoma of the lung in North America. Lung Cancer. 2005; 49 (2): 225–231. DOI: 10.1016/j.lungcan.2005.02.011.

15. Giaccone G., Herbst R.S., Manegold C. et al. Gefitinib in combination with gemcitabine and cisplatin in advanced non-small-cell lung cancer: a phase III trial–INTACT 1. J. Clin. Oncol. 2004; 22 (5): 777–784. DOI: 10.1200/JCO.2004.08.001.

16. Herbst R.S., Giaccone G., Schiller J.H. et al. Gefitinib in combination with paclitaxel and carboplatin in advanced non-small-cell lung cancer: a phase III trial–INTACT 2. J. Clin. Oncol. 2004; 22 (5): 785–794. DOI: 10.1200/JCO.2004.07.215.

17. Kim E.S., Hirsh V., Mok T. et al. Gefitinib versus docetaxel in previously treated non-small-cell lung cancer (INTEREST): a randomised phase III trial. Lancet. 2008; 372 (9652): 1809–1818. DOI: 10.1016/S0140-6736(08)61758-4.

18. Maruyama R., Nishiwaki Y., Tamura T. et al. Phase III study, V-15-32, of gefitinib versus docetaxel in previously treated Japanese patients with non-small-cell lung cancer. J. Clin. Oncol. 2008; 26 (26): 4244–4252. DOI: 10.1200/JCO.2007.15.0185.

19. Lee D.H., Park K., Kim J.H. et al. Randomized phase III trial of gefitinib versus docetaxel in non-small cell lung cancer patients who have previously received platinum-based chemotherapy. Clin. Cancer Res. 2010; 16 (4): 1307–1314. DOI: 10.1158/1078-0432.CCR-09-1903.

20. Thatcher N., Chang A., Parikh P. et al. Gefitinib plus best supportive care in previously treated patients with refractory advanced non-small-cell lung cancer: results from a randomised, placebo-controlled, multicentre study (Iressa Survival Evaluation in Lung Cancer). Lancet. 2005; 366 (9496): 1527–1537. DOI: 10.1016/S0140-6736(05)67625-8.

21. Shepherd F.A., Rodrigues Pereira J., Ciuleanu T. et al. Erlotinib in previously treated non-small-cell lung cancer. N. Engl. J. Med. 2005; 353 (2): 123–132. DOI: 10.1056/NEJMoa050753.

22. Shea M., Costa D.B., Rangachari D. Management of advanced non-small cell lung cancers with known mutations or rearrangements: latest evidence and treatment approaches. Ther. Adv. Respir. Dis. 2016; 10 (2): 113–129. DOI: 10.1177/1753465815617871.

23. Sequist L.V., Yang J.C.H., Yamamoto N. et al. Phase III study of afatinib or cisplatin plus pemetrexed in patients with metastatic lung adenocarcinoma with EGFR mutations. J. Clin. Oncol. 2013; 31 (27): 3327–3334. DOI: 10.1200/JCO.2012.44.2806.

24. Mok T.S., Wu Y.L., Thongprasert S. et al. Gefitinib or carboplatin-paclitaxel in pulmonary adenocarcinoma. N. Engl. J. Med. 2009; 361 (10): 947–957. DOI: 10.1056/NEJMoa0810699.

25. Mitsudomi T., Morita S., Yatabe Y. et al. Gefitinib versus cisplatin plus docetaxel in patients with non-small-cell lung cancer harbouring mutations of the epidermal growth factor receptor (WJTOG3405): an open label, randomised phase 3 trial. Lancet Oncol. 2010; 11 (2): 121–128. DOI: 10.1016/S1470-2045(09)70364-X.

26. Maemondo M., Inoue A., Kobayashi K. et al. Gefitinib or chemotherapy for non-small-cell lung cancer with mutated EGFR. N. Engl. J. Med. 2010; 362 (25): 2380–2388. DOI: 10.1056/NEJMoa0909530.

27. Zhou C., Wu Y.L., Chen G. et al. Erlotinib versus chemotherapy as first-line treatment for patients with advanced EGFR mutation-positive non-small-cell lung cancer (OPTIMAL, CTONG-0802): a multicentre, open-label, randomised, phase 3 study. Lancet Oncol. 2011; 12 (8): 735–742. DOI: 10.1016/S1470-2045(11)70184-X.

28. Rosell R., Carcereny E., Gervais R. et al. Erlotinib versus standard chemotherapy as first-line treatment for European patients with advanced EGFR mutation-positive non-smallcell lung cancer (EURTAC): a multicentre, open-label, randomised phase 3 trial. Lancet Oncol. 2012; 13 (3): 239–246. DOI: 10.1016/S1470-2045(11)70393-X.

29. Yeo W.L., Riely G.J., Yeap B.Y. et al. Erlotinib at a dose of 25 mg daily for non-small cell lung cancers with EGFR mutations. J. Thorac. Oncol. 2010; 5 (7): 1048–1053. DOI: 10.1097/JTO.0b013e3181dd1386.

30. Janne P.A., Yang J.C.H., Kim D.W. et al. AZD9291 in EGFR inhibitor-resistant non-small-cell lung cancer. N. Engl. J. Med. 2015; 372 (18): 1689–1699. DOI: 10.1056/NEJMoa1411817.

31. Sequist L.V., Soria J.C., Goldman J.W. et al. Rociletinib in EGFR-mutated non-small-cell lung cancer. N. Engl. J. Med. 2015; 372 (18): 1700–1709. DOI: 10.1056/NEJMoa1413654.

32. Ramalingam S.S., Yang J.C.H., Lee C.K. et al. Osimertinib as first-line treatment of EGFR mutation-positive advanced non-small-cell lung cancer. J. Clin. Oncol. 2018; 36 (9): 841–849. DOI: 10.1200/JCO.2017.74.7576.

33. Kwak E.L., Bang Y.J., Camidge D.R. et al. Anaplastic lymphoma kinase inhibition in non-small-cell lung cancer. N. Engl. J. Med. 2010; 363 (18): 1693–1703. DOI: 10.1056/NEJMoa1006448.

34. Camidge D.R., Bang Y.J., Kwak E.L. et al. Activity and safety of crizotinib in patients with ALK-positive non-small-cell lung cancer: updated results from a phase 1 study. Lancet Oncol. 2012; 13 (10): 1011–1019. DOI: 10.1016/S1470-2045(12)70344-3.

35. Shaw A.T., Kim D.W., Nakagawa K. et al. Crizotinib versus chemotherapy in advanced ALK-positive lung cancer. N. Engl. J. Med. 2013; 368 (25): 2385–2394. DOI: 10.1056/NEJMoa1214886.

36. Solomon B.J., Mok T., Kim D.W. et al. First-line crizotinib versus chemotherapy in ALK-positive lung cancer. N. Engl. J. Med. 2014; 371 (23): 2167–2177. DOI: 10.1056/NEJMoa1408440.

37. Shaw A.T., Kim D.W., Mehra R. et al. Ceritinib in ALKrearranged non-small-cell lung cancer. N. Engl. J. Med. 2014; 370 (13): 1189–1197. DOI: 10.1056/NEJMoa1311107.

38. Soria J.C., Tan D.S.W., Chiari R. et al. First-line ceritinib versus platinum-based chemotherapy in advanced ALKrearranged non-small-cell lung cancer (ASCEND-4): a randomised, open-label, phase 3 study. Lancet. 2017; 389 (10072): 917–929. DOI: 10.1016/S0140-6736(17)30123-X.

39. Hirsch F.R., Suda K., Wiens J. et al. New and emerging targeted treatments in advanced non-small-cell lung cancer. Lancet. 2016; 388 (10048): 1012–1024. DOI: 10.1016/S0140-6736(16)31473-8.

40. Peters S., Camidge D.R., Shaw A.T. et al. Alectinib versus crizotinib in untreated ALK-positive non-small-cell lung cancer. N. Engl. J. Med. 2017; 377 (9): 829–838. DOI: 10.1056/NEJMoa1704795.

41. Gettinger S.N., Bazhenova L.A., Langer C.J. et al. Activity and safety of brigatinib in ALK-rearranged non-small-cell lung cancer and other malignancies: a single-arm, openlabel, phase 1/2 trial. Lancet Oncol. 2016; 17 (12): 1683– 1696. DOI: 10.1016/S1470-2045(16)30392-8.

42. Planchard D., Kim T.M., Mazieres J. et al. Dabrafenib in patients with BRAF(V600E)-positive advanced non-smallcell lung cancer: a single-arm, multicentre, open-label, phase 2 trial. Lancet Oncol. 2016; 17 (5): 642–650. DOI: 10.1016/S1470-2045(16)00077-2.

43. Planchard D., Besse B., Groen H.J.M. et al. Dabrafenib plus trametinib in patients with previously treated BRAF(V600E)-mutant metastatic non-small cell lung cancer: an open-label, multicentre phase 2 trial. Lancet Oncol. 2016; 17 (7): 984–993. DOI: 10.1016/S1470-2045(16)30146-2.

44. Planchard D., Smit E.F., Groen H.J.M. et al. Dabrafenib plus trametinib in patients with previously untreated BRAF(V600E)-mutant metastatic non-small-cell lung cancer: an open-label, phase 2 trial. Lancet Oncol. 2017; 18 (10): 1307–1016. DOI: 10.1016/S1470-2045(17)30679-4.

45. Lehman J.M., Gwin M.E., Massion P.P. Immunotherapy and targeted therapy for small cell lung cancer: there is hope. Curr. Oncol. Rep. 2017; 19 (7): 49. DOI: 10.1007/s11912-017-0609-2.

46. Schoffski P., Besse B., Gauler T. et al. Efficacy and safety of biweekly i.v. administrations of the Aurora kinase inhibitor danusertib hydrochloride in independent cohorts of patients with advanced or metastatic breast, ovarian, colorectal, pancreatic, small-cell and non-small-cell lung cancer: a multitumour, multi-institutional phase II study. Ann Oncol. 2015; 26 (3): 598–607. DOI: 10.1093/annonc/mdu566.

47. Melichar B., Adenis A., Lockhart A.C. et al. Safety and activity of alisertib, an investigational aurora kinase A inhibitor, in patients with breast cancer, small-cell lung cancer, non-small-cell lung cancer, head and neck squamouscell carcinoma, and gastro-oesophageal adenocarcinoma: a five-arm phase 2 study. Lancet Oncol. 2015; 16 (4): 395–405. DOI: 10.1016/S1470-2045(15)70051-3.