Оптимизация лечебной тактики с использованием таргетной терапии при диссеминированном и местнораспространенном немелкоклеточном раке легкого


А.В. Смолин (1), Е.В. Крюков (1), А.В. Конев (1), С.Н. Николаева (1), Ю.Е. Шаманская (1), А.В. Горбачева (2), А.Г. Матвеев (1)

(1) ФГКУ «Главный военный клинический госпиталь им. Н.Н. Бурденко» Минобороны России, Москва (2) Кафедра факультетской хирургии-2, ФГБОУ ВО «Первый МГМУ им. И.М. Сеченова» Минздрава РФ, Москва
Широкое распространение в последнее десятилетие молекулярно-генетических методов исследования вскрыло новые механизмы канцерогенеза. Часть из этих механизмов оказалась пригодной для терапевтического воздействия. Обнаружено несколько ключевых сигнальных каскадов, активация которых напрямую связана с пролиферацией, миграцией и метастазированием опухолевых клеток. Экспрессия рецепторов к эпидермальному фактору роста (EGFR – epidermal growth factor receptor) обнаруживается при немелкоклеточном раке легкого (НМРЛ) в 85–90%. Вследствие этого именно EGFR был первым рецептором, предложенным как мишень для противоопухолевой терапии. Стандартные платиновые комбинации при раке легкого к концу ХХ в. полностью себя исчерпали. Появление новых противоопухолевых химиотерапевтических препаратов создало дополнительные возможности, однако ни одна из известных комбинаций не имела преимуществ перед другими. Только появление таргетной терапии внесло существенные изменения в эффективность проводимого лечения. Одним из первых таргетных препаратов, зарегистрированных при НМКРЛ, стал бевацизумаб.

Литература


1. Morgensztern D., Waqar S., Subramanian J., Gao F., Govindan R. Improving Survival for Stage IV Non-small Cell Lung Cancer: A Surveillance, Epidemiology, and End Results Survey from 1990 to 2005. J. Thor. Oncol. 2009;4:1524–29.

2. Mitsudomi T., Yatabe Y. Mutations of the epi-dermal growth factor receptor gene and related genes as determinants of epidermal growth factor receptor tyrosine kinase inhibitors sensiti-vity in lung cancer. Cancer Sci. 2007;98:1817–24.

3. Lynch T.J., Bell D.W., Sordella R., Gurubhagavatula S., Okimoto R.A., Brannigan B.W., Harris P.L., Haserlat S.M., Supko J.G., Haluska F.G., Louis D.N., Christiani D.C., Settleman J., Haber DA. Activating mutations in the epidermal growth factor receptor underlying responsiveness of non-small-cell lung cancer to gefitinib. N. Engl. J. Med. 2004;350:2129–39.

4. Paez J.G., Jänne P.A., Lee J.C., Tracy S., Greulich H., Gabriel S., Herman P., Kaye F.J., Lindeman N., Boggon T.J., Naoki K., Sasaki H., Fujii Y., Eck M.J., Sellers W.R., Johnson B.E., Meyerson M. EGFR mutations in lung cancer: correlation with clinical response to gefitinib therapy. Science. 2004;304:1497–500.

5. Yasuda H., Kobayashi S., Costa D.B. EGFR exon 20 insertion mutations in non-small-cell lung cancer: preclinical data and clinical implications. Lancet. Oncol. 2012;13:23–31.

6. Shigematsu H., Lin L., Takahashi T., Nomura M., Suzuki M., Wistuba I.I., Fong K.M., Lee H., Toyooka S., Shimizu N., Fujisawa T., Feng Z., Roth J.A., Herz J., Minna J.D., Gazdar A.F. Clinical and Biological Features Associated With Epidermal Growth Factor Receptor Gene Mutations in Lung Cancers. JNCI. 2005;97(5):339–46.

7. Catalogue of Somatic Mutations in Cancer, release version 76.

8. Nguyen K.S., Kobayashi S., Costa D.B. Acquired resistance to epidermal growth factor receptor tyrosine kinase inhibitors in non-small-cell lung cancers dependent on the epidermal growth factor receptor pathway. Clin. Lung Cancer. 2009;10(4):281–89.

9. Rosell R., Carcereny E., Gervais R., et al.; Spanish Lung Cancer Group in collaboration with Groupe Français de Pneumo-Cancérologie and Associazione Italiana Oncologia Toracica.. Erlotinib versus standard chemotherapy as first-line treatment for European patients with advanced EGFR mutation-positive non-small-cell lung cancer (EURTAC): a multicentre, open-label, randomised phase 3 trial. Lancet. Oncol. 2012;13:239–46.

10. Schwander B., de Castro C.J., Heigener D., Wright E., Bischoff H., Walzer S. Comparative Effectiveness Assessment of Erlotinib vs Gefitinib in First-Line EGFR Activating Mutation Positive Non-Small Cell Lung Cancer; ISPOR 16th Annual International Meeting; Value in Health. 2011;14(3):155.

11. Lee V.W.Y., Lee V., Schwander B. Comparative Effectiveness and Cost-Effectiveness Assessment of Erlotinib versus Gefitinib in First-Line Treatment of EGFR Activating Mutation Positive Non-Small Cell Lung Cancer for Hong Kong; poster presentation (PCN21) at the ISPOR 5th Asia Pacific Conference, Taipei, Taiwan, September 2012.

12. Kobayashi Y., Togashi Y., Yatabe Y., Mizuuchi H., Jangchul P., Kondo C., Shimoji M., Sato K., Suda K., Tomizawa K., Takemoto T., Hida T., Nishio K., Mitsudomi T. EGFR exon 18 mutations in lung cancer: molecular predictors of augmented sensitivity to afatinib and neratinib as compared with first or third generation TKIs. Clin. Cancer Res. 2015;21:5305–13.

13. Wu J.Y., Yu C.J., Chang Y.C., Yang C.H., Shih J.Y., Yang P.C. Effectiveness of tyrosine kinase inhibitors on “uncommon” epidermal growth factor receptor mutations of unknown clinical significance in non-small cell lung cancer. Clin. Cancer Res. 2011;17:3812–21.

14. Roengvoraphoj M., Tsongalis G.J., Dragnev K.H., Rigas J.R. Epidermal growth factor receptor tyrosine kinase inhibitors as initial therapy for non-small cell lung cancer: focus on epidermal growth factor receptor mutation testing and mutation-positive patients. Cancer Treat. Rev. 2013;39:839–50.

15. Shi Y., Au J.S., Thongprasert S., Srinivasan S., Tsai C.M., Khoa M.T., Heeroma K., Itoh Y., Cornelio G., Yang P.C. A prospective, molecular epidemiology study of EGFR mutations in Asian patients with advanced non-small-cell lung cancer of adenocarcinoma histology (PIONEER). J. Thorac. Oncol. 2014;9:154–62.

16. Lee B., Lee T., Lee S.H., Choi Y.L., Han J. Clinicopathologic characteristics of EGFR, KRAS, and ALK alterations in 6595 lung cancers. Oncotarget. 2016;7(17):23874–84.

17. Maemondo M., Inoue A., Kobayashi K., Sugawara S., Oizumi S., Isobe H., Gemma A., Harada M., Yoshizawa H., Kinoshita I., Fujita Y., Okinaga S., Hirano H., Yoshimori K., Harada T., Ogura T., Ando M., Miyazawa H., Tanaka T., Saijo Y., Hagiwara K., Morita S., Nukiwa T. Gefitinib or chemotherapy for non-small-cell lung cancer with mutated EGFR. N. Engl. J. Med. 2010;362:2380–88.

18. Mitsudomi T., Morita S., Yatabe Y., Negoro S., Okamoto I., Tsurutani J., Seto T., Satouchi M., Tada H., Hirashima T., Asami K., Katakami N., Takada M., Yoshioka H., Shibata K., Kudoh S., Shimizu E., Saito H., Toyooka S., Nakagawa K., Fukuoka M. 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;11:121–8.

19. Zhou C., Wu Y.L., Chen G., Feng J., Liu X.Q., Wang C., Zhang S., Wang J., Zhou S., Ren S., Lu S., Zhang L., Hu C., Hu C., Luo Y., Chen L., Ye M., Huang J., Zhi X., Zhang Y., Xiu Q., Ma J., Zhang L., You C. 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;12:735–42.

20. Sequist L.V., Yang J.C., Yamamoto N., O’Byrne K., Hirsh V., Mok T., Geater S.L., Orlov S., Tsai C.M., Boyer M., Su W.C., Bennouna J., Kato T., Gorbunova V., Lee K.H., Shah R., Massey D., Zazulina V., Shahidi M., Schuler M. Phase III study of afatinib or cisplatin plus pemetrexed in patients with metastatic lung adenocarcinoma with EGFR mutations. J. Clin. Oncol. 2013;31:3327–34.

21. Wu Y.L., Zhou C., Hu C.P., Feng J., Lu S., Huang Y., Li W., Hou M., Shi J.H., Lee K.Y., Xu C.R., Massey D., Kim M., Shi Y., Geater S.L. Afatinib versus cisplatin plus gemcitabine for first-line treatment of Asian patients with advanced non-small-cell lung cancer harbouring EGFR mutations (LUX-Lung 6): an open-label, randomised phase 3 trial. Lancet. Oncol. 2014;15:213–22.

22. Mok T.S., Wu Y.L., Thongprasert S., Yang C.H., Chu D.T., Saijo N., Sunpaweravong P., Han B., Margono B., Ichinose Y., Nishiwaki Y., Ohe Y., Yang J.J., Chewaskulyong B., Jiang H., Duffield E.L., Watkins C.L., Armour A.A., Fukuoka M. Gefitinib or carboplatin-paclitaxel in pulmo-nary adenocarcinoma. N. Engl. J. Med. 2009;361:947–57.

23. Lee C.K., Wu Y.L., Ding P.N., Lord S.J., Inoue A., Zhou C., Mitsudomi T., Rosell R., Pavlakis N., Links M., Gebski V., Gralla R.J., Yang J.C. Impact of specific epidermal growth factor receptor (EGFR) mutations and clinical characteristics on outcomes after treatment with EGFR tyrosine kinase inhibitors versus chemotherapy in EGFR-mutant lung cancer: a meta-analysis. J. Clin. Oncol. 2015;33:1958–65.

24. Kobayashi Y., Mitsudomi T. Not all epidermal growth factor receptor mutations in lung cancer are created equal: Perspectives for individualized treatment strategy. Cancer Sci. 2016 Jun 20.

25. Arcila M.E., Nafa K., Chaft J.E., Rekhtman N., Lau C., Reva B.A., Zakowski M.F., Kris M.G., Ladanyi M. EGFR exon 20 insertion mutations in lung adenocarcinomas: prevalence, molecular heterogeneity, and clinicopathologic characteristics. Mol. Cancer Ther. 2013;12:220–29.

26. Zhu C.Q., da Cunha Santos G., Ding K., Sakurada A., Cutz J.C., Liu N., Zhang T., Marrano P., Whitehead M., Squire J.A., Kamel-Reid S., Seymour L., Shepherd F.A., Tsao M.S. Role of KRAS and EGFR As Biomarkers of Response to Erlotinib in National Cancer Institute of Canada Clinical Trials Group Study BR.21. J. Clin. Oncol. 2008;26:4268–75.

27. Shepherd F.A., Rodrigues Pereira J., Ciuleanu T., Tan E.H., Hirsh V., Thongprasert S., Campos D., Maoleekoonpiroj S., Smylie M., Martins R., van Kooten M., Dediu M., Findlay B., Tu D., Johnston D., Bezjak A., Clark G., Santabárbara P., Seymour L. Erlotinib in previously treated non-small-cell lung cancer. N. Engl. J. Med. 2005;353:123–32.

28. Смолин А.В., Борисов В.И., Орлов С.В., Гуторов С.Л., Феденко А.А., Карасева Н.А., Халиярова Д.Д. Результаты российского многоцентрового исследования по изучению возможности использования клинических предикторов для отбора больных немелкоклеточным раком легкого на терапию эрлотинибом. Современная онкология. 2011;4:26–32.

29. Yasuda H., Kobayashi S., Costa D.B. EGFR exon 20 insertion mutations in non-small-cell lung cancer: preclinical data and clinical implications. Lancet. Oncol. 2012;13:e23–31.

30. Yasuda H., Park E., Yun C.H., Sng N.J., Lucena-Araujo A.R., Yeo W.L., Huberman M.S., Cohen D.W., Nakayama S., Ishioka K., Yamaguchi N., Hanna M., Oxnard G.R., Lathan C.S., Moran T., Sequist L.V., Chaft J.E., Riely G.J., Arcila M.E., Soo R.A., Meyerson M., Eck M.J., Kobayashi S.S., Costa D.B. Structural, biochemical, and clinical characterization of epidermal growth factor receptor (EGFR) exon 20 insertion mutations in lung cancer. Sci. Transl. Med. 2013;5:216ra177.

31. Yang J.C., Sequist L.V., Geater S.L., Tsai C.M., Mok T.S., Schuler M., Yamamoto N., Yu C.J., Ou S.H., Zhou C., Massey D., Zazulina V., Wu Y.L. Clinical activity of afatinib in patients with advanced non-small-cell lung cancer harbouring uncommon EGFR mutations: a combined post‐hoc analysis of LUX-Lung 2, LUX-Lung 3, and LUX-Lung 6. Lancet. Oncol. 2015;16:830–38.

32. Hirano T., Yasuda H., Tani T., Hamamoto J., Oashi A., Ishioka K., Arai D., Nukaga S., Miyawaki M., Kawada I., Naoki K., Costa D.B., Kobayashi S.S., Betsuyaku T., Soejima K. In vitro modeling to determine mutation specificity of EGFR tyrosine kinase inhibitors against clinically relevant EGFR mutants in non-small-cell lung cancer. Oncotarget. 2015;6:38789–803.

33. Yang M., Xu X., Cai J., Ning J., Wery J.P., Li Q.X. NSCLC harboring EGFR exon‐20 insertions after the regulatory C-helix of kinase domain responds poorly to known EGFR inhibitors. Int. J. Cancer. 2016;139:171–76.

34. Banno E., Togashi Y., Nakamura Y., Chiba M. Kobayashi Y., Hayashi H., Terashima M., de Velasco M.A., Sakai K., Fujita Y., Mitsudomi T., Nishio K. Sensitivities to various epidermal growth factor receptor-tyrosine kinase inhibitors of uncommon epidermal growth factor receptor mutations L861Q and S768I: What is the optimal epidermal growth factor receptor-tyrosine kinase inhibitor? Cancer Science. 2016;107(8):1134–40.

35. Wu J.Y., Wu S.G., Yang C.H., Gow C.H., Chang Y.L., Yu C.J., Shih J.Y., Yang P.C. Lung cancer with epidermal growth factor receptor exon 20 mutations is associated with poor gefitinib treatment response. Clin. Cancer Res. 2008;14:4877–82.

36. Beau-Faller M., Prim N., Ruppert A.M., Nanni-Metéllus I., Lacave R., Lacroix L., Escande F., Lizard S., Pretet J.L., Rouquette I., de Crémoux P., Solassol J., de Fraipont F., Bièche I., Cayre A., Favre-Guillevin E., Tomasini P., Wislez M., Besse B., Legrain M., Voegeli A.C., Baudrin L., Morin F., Zalcman G., Quoix E., Blons H., Cadranel J. Rare EGFR exon 18 and exon 20 mutations in non-small-cell lung cancer on 10 117 patients: a multicentre observational study by the French ERMETIC-IFCT network. Ann. Oncol. 2014;25:126–31.

37. Watanabe S., Minegishi Y., Yoshizawa H., Maemondo M., Inoue A., Sugawara S., Isobe H., Harada M., Ishii Y., Gemma A., Hagiwara K., Kobayashi K. Effectiveness of gefitinib against non-small-cell lung cancer with the uncommon EGFR mutations G719X and L861Q. J. Thorac. Oncol. 2014;9:189–94.

38. Otsuka T., Mori M., Yano Y., Uchida J., Nishino K., Kaji R., Hata A., Hattori Y., Urata Y., Kaneda T., Tachihara M., Imamura F., Katakami N., Negoro S., Morita S., Yokota S. Effectiveness of tyrosine kinase inhibitors in Japanese patients with non-small cell lung cancer harboring minor epidermal growth factor receptor mutations: results from a multicenter retrospective study (HANSHIN Oncology Group 0212). Anticancer. Res. 2015;35:3885–91.

39. Chiu C.H., Yang C.T., Shih J.Y., Huang M.S., Su W.C., Lai R.S., Wang C.C., Hsiao S.H., Lin Y.C., Ho C.L., Hsia T.C., Wu M.F., Lai C.L., Lee K.Y., Lin C.B., Yu-Wung Yeh D., Chuang C.Y., Chang F.K., Tsai C.M., Perng R.P., Chih-Hsin Yang J. Epidermal growth factor receptor tyrosine kinase inhibitor treatment response in advanced lung adenocarcinomas with G719X/L861Q/S768I mutations. J. Thorac. Oncol. 2015;10:793–99.

40. Gridelli C., Ciardiello R., Feld R., et al. International multicenter randomized phase III study of first-line erlotinib (E) followed by second-line cisplatin plus gemcitabine (CG) versus first-line CG followed by second-line E in advanced non-small cell lung cancer (aNSCLC): The TORCH trial (abstract #7508). J. Clin. Oncol. 2010;28:15s.

41. Paz-Ares L., Soulières D., Moecks J., Bara I., Mok T., Klughammer B. Pooled analysis of clinical outcome for EGFR TKI-treated patients with EGFR mutation-positive NSCLC. J. Cell. Mol. Med. 2014;18(8):1519–39.

42. Sandler A., Gray R., Perry M.C., Brahmer J., Schil-ler J.H., Dowlati A., Lilenbaum R., Johnson D.H. Paclitaxel-carboplatin alone or with bevacizumab for non-small-cell lung cancer. N. Engl. J. Med. 2006;355(24):2542–50.

43. Nadler E., Yu E., Ravelo A., Sing A., Forsyth M., Gruschkus S. Bevacizumab treatment to progression after chemotherapy: outcomes from a U.S. community practice network. Oncologist. 2011;16:486–96.

44. Li S., Yang H., Guo Y., Wei F., Yang X., Li D., Li M., Xu W., Li W., Sun L., Gao Y., Wang Y. Comparative efficacy and safety of urate-lowering therapy for the treatment of hyperuricemia: a systematic review and network meta-analysis. Scientific Reports. 2016;6:33082.

45. Suda K., Murakami I., Sakai K., Mizuuchi H., Shimizu S., Sato K., Tomizawa K., Tomida S., Yatabe Y., Nishio K., Mitsudomi T. Small cell lung cancer transformation and T790M mutation: complimentary roles in acquired resistance to kinase inhibitors in lung cancer. Scientific Reports. 2015;5:14447.

46. Sequist L.V., Waltman B.A., Dias-Santagata D., Digumarthy S., Turke A.B., Fidias P., Bergethon K., Shaw A.T., Gettinger S., Cosper A.K., Akhavanfard S., Heist R.S., Temel J., Christensen J.G., Wain J.C., Lynch T.J., Vernovsky K., Mark E.J., Lanuti M., Iafrate A.J., Mino-Kenudson M., Engelman J.A. Genotypic and Histological Evolution of Lung Cancers Acquiring Resistance to EGFR Inhibitors. Sci. Transl. Med. 2011;3(75):75ra26.

47. Yang J., Ramalingam S.S., Jänne P.A., Cantarini M., Mitsudomi T. Osimertinib (AZD9291) in pre-treated pts with T790M-positive advanced NSCLC: updated Phase 1 (P1) and pooled Phase 2 (P2) results. J. Thorac. Oncol. 2016;11:152–53.

48. Gandara D.R., Li T., Lara P.N., Kelly K., Riess J.W., Redman M.W., Mack P.C. Acquired Resistance to Targeted Therapies against Oncogene-Driven Non-Small Cell Lung Cancer: Approach to Subtyping Progressive Disease and Clinical Implications. Clinical. Lung. Cancer. 2014;15(1):1–6.

49. Weickhardt A.J., Scheier B., Burke J.M., Gan G., Lu X., Bunn P.A. Jr., Aisner D.L., Gaspar L.E., Kavanagh B.D., Doebele R.C., Camidge D.R. Local ablative therapy of oligoprogressive disease prolongs disease control by tyrosine kinase inhibitors in oncogene addicted non-small cell lung cancer. J. Thoracic Oncology : official publication of the International Association for the Study of Lung Cancer. 2012;7(12):1807–14.


Об авторах / Для корреспонденции


А.В. Смолин – начальник радиологического центра ФГКУ «Главный военный клинический госпиталь им. Н.Н. Бурденко» Минобороны России, Москва; e-mail: smolinGVKG@gmail.com


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