Журнал "Медицинский совет" №9/2020



DOI: 10.21518/2079-701X-2020-9-80-93



Подходы к терапии метастатической меланомы кожи в 2020 году: динамичное движение вперед - «Гинекология»
 И.В. Самойленко, ORCID: 0000-0001-7150-5071, e-mail: i.samoylenko@ronc.ru, 
 Л.В. Демидов, ORCID: 0000-0002-8562-6082, e-mail: l.demidov@ronc.ru, Национальный медицинский исследовательский центр онкологии им. Н.Н. Блохина


Выбор терапии первой линии метастатической меланомы кожи в последние несколько лет стал довольно непростой задачей: у практикующего онколога появились лекарственные препараты различных классов с различным механизмом действия – блокаторы иммунных чек-пойнтов и ингибиторы тирозинкиназ BRAF/MEK. В данной работе авторы постарались систематизировать собственный опыт и текущие научные сведения о лечении больных метастатической меланомой кожи в первой и последующих линиях терапии. В работе обсуждается важность правильной исходной оценки состояния пациента и распространенности процесса, роль доступных в настоящее время биомаркеров при метастатической меланоме кожи, а также эффективность и безопасность возможных вариантов первой линии терапии данного заболевания. Ввиду отсутствия данных прямого сравнения комбинированной иммунотерапии, комбинированной таргетной терапии, тройной комбинации блокаторов BRAFi + MEKi + aPDl1 и монотерапии aPD1, полученных в результате рандомизированных исследований, нам приходится проводить параллели между исследованиями с различными диагнозами и различными популяциями пациентов. Поскольку практикующему онкологу в своей ежедневной работе приходится выполнять те же действия, мы полагаем, что наш обзор будет для этих врачей весьма полезен. В статье также обсуждаются возможности применения лекарственной терапии во второй и последующих линиях и успешная в ряде случаев стратегия возврата к предыдущему лечению. В качестве иллюстрации успеха тактики последовательной терапии различными препаратами приводится клиническое наблюдение пациентки с метастатической меланомой кожи стопы, которая наблюдается в нашем отделении с 2010 г. Клиническое наблюдение демонстрирует успех возврата к некоторым, ранее уже применяемым линями терапии, в т. ч. после развития прогрессирования на них.




Для цитирования:


Самойленко И.В., Демидов Л.В. Подходы к терапии метастатической меланомы кожи в 2020 году: динамичное движение вперед. Медицинский совет. 2020;(9):80–93. doi: 10.21518/2079-701X-2020-9-80-93



Конфликт интересов: авторы заявляют об отсутствии конфликта интересов.



Approaches to metastatic skin melanoma therapy in 2020: a dynamic way forward





 Igor V. Samoylenko, ORCID: 0000-0001-7150-5071, e-mail: i.samoylenko@ronc.ru, 
 Lev V. Demidov, ORCID: 0000-0002-8562-6082, e-mail: l.demidov@ronc.ru, N.N. Blokhin National Medical Research Center of Oncology


The choice of first-line therapy for metastatic skin melanoma has become quite a difficult task in the last few years: a practicing oncologist has got drugs of different classes with different mechanisms of action – immune checkpoint blockers and BRAF/MEK tyrosine kinase inhibitors. In this study, the authors have tried to systematize their own experience and current scientific information about the treatment of patients with metastatic skin melanoma in the first and subsequent lines of therapy. The paper discusses the importance of correct initial assessment of the patient’s condition and prevalence of the process, the role of currently available biomarkers in metastatic skin melanoma, as well as the effectiveness and safety of possible first-line therapy options for this disease. Due to the lack of data for direct comparison of combined immunotherapy, combined targeted therapy, triple combination of BRAFi + MEKi + aPDl1 blockers and aPD1 monotherapy obtained from randomized studies, we have to draw parallels between studies with different diagnoses and different patient populations. Since the practicing oncologist has to do the same thing in his or her daily work, we believe that our review will be very useful for these doctors. The article also discusses the possibility of using drug therapy in the second and subsequent lines and a successful strategy to return to previous treatment in some cases. The clinical observation of a patient with metastatic foot skin melanoma, which has been observed in our department since 2010, is given as an illustration of the success of sequential treatment tactics with different drugs. Clinical observation shows the success of returning to some previously used therapy lines, including after the progression on them.


For citation:


Samoylenko I.V., Demidov L.V. Approaches to treatment of metastatic skin melanoma in 2020: a dynamic way forward. Meditsinskiy sovet = Medical Council. 2020;(9):80–93. (In Russ.) doi: 10.21518/2079-701X-2020-9-80-93



Conflict of interest: the authors declare that there is no conflict of interest.


Загрузить файл в формате PDF



Список литературы / References



  2. Balch C.M., Gershenwald J.E., Soong S.J., Thompson J.F., Atkins M.B., Byrd D.R. et al. Final version of 2009 AJCC melanoma staging and classification. J Clin Oncol. 2009;27(36):6199-6206. https://doi.org/10.1200/JCO.2009.23.4799.
  3. Brierley J.D., Gospodarowicz M.K., Wittekind C. (eds.). TNM classification of malignant tumors. 8th ed. Oxford, UK: John Wiley & Sons, Inc; 2017.
  4. Gershenwald J.E., Scolyer R.A., Hess K.R., Sondak V.K., Long G.V., Ross M.I. et al. Melanoma staging: Evidence-based changes in the American Joint Committee on Cancer eighth edition cancer staging manual. CA Cancer J Clin. 2017;67(6):472-492. https://doi.org/10.3322/caac.21409.
  5. Gastman B.R., Gerami P., Kurley S.J., Cook R.W., Leachman S., Vetto J.T. Identification of patients at risk of metastasis using a prognostic 31-gene expression profile in subpopulations of melanoma patients with favorable outcomes by standard criteria. J Am Acad Dermatol. 2019;80(1):149- 157. https://doi.org/10.1016/j.jaad.2018.07.028.
  6. Dickson P.V., Gershenwald J.E. Staging and prognosis of cutaneous melanoma. Surg Oncol Clin N Am. 2011;20(1):1-17. https://doi.org/10.1016/j.soc.2010.09.007.
  7. Tejera-Vaquerizo A., Barrera-Vigo M.V., Lopez-Navarro N., Herrera-Ceballos E. Growth rate as a prognostic factor in localized invasive cutaneous melanoma. J Eur Acad Dermatol Venereol. 2010;24(2):147-154. https://doi.org/10.1111/j.1468-3083.2009.03367.x.
  8. Gualdi G., Panarese F., Meogrossi G., Marchioni M., De Tursi M., Di Marino P. et al. Speed Rate (SR) as a new dynamic index of melanoma behavior. Pigment Cell Melanoma Res. 2020. https://doi.org/10.1111/pcmr.12890.
  9. Giuffrida R., Conforti C., Schmid K., Deinlein T., Zalaudek I. Rate of growthA novel surrogate marker for high-risk cutaneous squamous cell carcinoma? A case report and review of the literature. Dermatol Ther. 2020;33(1):e13156. https://doi.org/10.1111/dth.13156.
  10. Menzer C., Menzies A.M., Carlino M.S., Reijers I., Groen E.J., Eigentler T. et al. Targeted Therapy in Advanced Melanoma With Rare BRAF Mutations. J Clin Oncol. 2019;37(33):3142-3151. https://doi.org/10.1200/JCO.19.00489.
  11. Richtig G., Hoeller C., Kashofer K., Aigelsreiter A., Heinemann A., Kwong L.N. et al. Beyond the BRAF(V)(600E) hotspot: biology and clinical implications of rare BRAF gene mutations in melanoma patients. Br J Dermatol. 2017;177(4):936-944. https://doi.org/10.1111/bjd.15436.
  12. Long G.V., Menzies A.M., Nagrial A.M., Haydu L.E., Hamilton A.L., Mann G.J. et al. Prognostic and clinicopathologic associations of oncogenic BRAF in metastatic melanoma. J Clin Oncol. 2011;29(10):1239-1246. https://doi.org/10.1200/JCO.2010.32.4327.
  13. Hodi F.S., Corless C.L., Giobbie-Hurder A., Fletcher J.A., Zhu M., MarinoEnriquez A. et al. Imatinib for melanomas harboring mutationally activated or amplified KIT arising on mucosal, acral, and chronically sun-damaged skin. J Clin Oncol. 2013;31(26):3182-3190. https://doi.org/10.1200/JCO.2012.47.7836.
  14. Dummer R., Schadendorf D., Ascierto P.A., Arance A., Dutriaux C., Di Giacomo A.M. et al. Binimetinib versus dacarbazine in patients with advanced NRAS-mutant melanoma (NEMO): a multicentre, open-label, randomised, phase 3 trial. Lancet Oncol. 2017;18(4):435-445. https://doi.org/10.1016/S1470-2045(17)30180-8.
  15. Larkin J., Chiarion-Sileni V., Gonzalez R., Grob J.J., Rutkowski P., Lao C.D. et al. Five-Year Survival with Combined Nivolumab and Ipilimumab in Advanced Melanoma. N Engl J Med. 2019;381(16):1535-1546. https://doi.org/10.1056/NEJMoa1910836.
  16. Prat A., Navarro A., Pare L., Reguart N., Galvan P., Pascual T. et al. ImmuneRelated Gene Expression Profiling After PD-1 Blockade in Non-Small Cell Lung Carcinoma, Head and Neck Squamous Cell Carcinoma, and Melanoma. Cancer Res. 2017;77(13):3540-3550. https://doi.org/10.1158/0008-5472.CAN-16-3556.
  17. Patel S.P., Kurzrock R. PD-L1 Expression as a Predictive Biomarker in Cancer Immunotherapy. Mol Cancer Ther. 2015;14(4):847-856. https://doi.org/10.1158/1535-7163.MCT-14-0983.
  18. Lee E.Y., Kulkarni R.P. Circulating biomarkers predictive of tumor response to cancer immunotherapy. Expert Rev Mol Diagn. 2019;19(10):895-904. https://doi.org/10.1080/14737159.2019.1659728.
  19. Carlino M.S., Long G.V., Schadendorf D., Robert C., Ribas A., Richtig E. et al. Outcomes by line of therapy and programmed death ligand 1 expression in patients with advanced melanoma treated with pembrolizumab or ipilimumab in KEYNOTE-006: A randomised clinical trial. Eur J Cancer. 2018;101:236-243. https://doi.org/10.1016/j.ejca.2018.06.034.
  20. Lebbe C., Meyer N., Mortier L., Marquez-Rodas I., Robert C., Rutkowski P. et al. Evaluation of Two Dosing Regimens for Nivolumab in Combination With Ipilimumab in Patients With Advanced Melanoma: Results From the Phase IIIb/IV CheckMate 511 Trial. J Clin Oncol. 2019;37(11):867-875. https://doi.org/10.1200/JCO.18.01998.
  21. Long G.V., Atkinson V., Cebon J.S., Jameson M.B., Fitzharris B.M., McNeil C.M. et al. Standard-dose pembrolizumab in combination with reduced-dose ipilimumab for patients with advanced melanoma (KEYNOTE-029): an open-label, phase 1b trial. Lancet Oncol. 2017;18(9):1202-1210. https://doi.org/10.1016/S1470-2045(17)30428-X.
  22. Wolchok J.D., Chiarion-Sileni V., Gonzalez R., Rutkowski P., Grob J.J., Cowey C.L. et al. Overall Survival with Combined Nivolumab and Ipilimumab in Advanced Melanoma. N Engl J Med. 2017;377(14):1345-1356. https://doi.org/10.1056/NEJMoa1709684.
  23. Brower V. Hyperprogressive disease with anti-PD-1 and anti-PD-L1. Lancet Oncol. 2016;17(12):e527. https://doi.org/10.1016/S1470-2045(16)30590-3.
  24. Champiat S., Dercle L., Ammari S., Massard C., Hollebecque A., Postel-Vinay S. et al. Hyperprogressive Disease Is a New Pattern of Progression in Cancer Patients Treated by Anti-PD-1/PD-L1. Clin Cancer Res. 2017;23(8):1920-1928. https://doi.org/10.1158/1078-0432.CCR-16-1741.
  25. Самойленко И.В., Жуликов Я.И., Демидов Л.В. Феномен гиперпрогрессирования опухолей на фоне применения блокаторов PD1: мифы или реальность? Фарматека. 2018;(12):22-28. https://doi.org/10.18565/pharmateca.2018.12.22-28.
  26. Robert C., Ribas A., Schachter J., Arance A., Grob J.J., Mortier L. et al. Pembrolizumab versus ipilimumab in advanced melanoma (KEYNOTE-006): post-hoc 5-year results from an open-label, multicentre, randomised, controlled, phase 3 study. Lancet Oncol. 2019;20(9):1239- 1251. https://doi.org/10.1016/S1470-2045(19)30388-2.
  27. Robert C., Larkin J., Ascierto P.A., Long G.V., Hassel J.C., Schadendorf D. et al. Characterization of complete responses (CRs) in patients with advanced melanoma (MEL) who received the combination of nivolumab (NIVO) and ipilimumab (IPI), NIVO or IPI alone. Ann Oncol. 2017;28:428-448. https://doi.org/10.1093/annonc/mdx377.
  28. Larkin J., Chiarion-Sileni V., Gonzalez R., Grob J.J., Cowey C.L., Lao C.D. et al. Combined Nivolumab and Ipilimumab or Monotherapy in Untreated Melanoma. N Engl J Med. 2015;373(1):23-34. https://doi.org/10.1056/NEJMoa1504030.
  29. Hamid O., Robert C., Daud A., Hodi F.S., Hwu W.-J., Kefford R. et al. 5-year survival outcomes in patients (pts) with advanced melanoma treated with pembrolizumab (pembro) in KEYNOTE-001. Journal of Clinical Oncology. 2018;36(15):9516. https://doi.org/10.1200/JCO.2018.36.15_suppl.9516.
  30. Daud A., Gill J., Kamra S., Chen L., Ahuja A. Indirect treatment comparison of dabrafenib plus trametinib versus vemurafenib plus cobimetinib in previously untreated metastatic melanoma patients. J Hematol Oncol. 2017;10(1):3. https://doi.org/10.1186/s13045-016-0369-8.
  31. Ascierto P.A., McArthur G.A., Dreno B., Atkinson V., Liszkay G., Di Giacomo A.M. et al. Cobimetinib combined with vemurafenib in advanced BRAF(V600)- mutant melanoma (coBRIM): updated efficacy results from a randomised, double-blind, phase 3 trial. Lancet Oncol. 2016;17(9):1248-1260. https://doi.org/10.1016/S1470-2045(16)30122-X.
  32. Robert C., Grob J.J., Stroyakovskiy D., Karaszewska B., Hauschild A., Levchenko E. et al. Five-Year Outcomes with Dabrafenib plus Trametinib in Metastatic Melanoma. N Engl J Med. 2019;381(7):626-636. https://doi.org/10.1056/NEJMoa1904059.
  33. McArthur G.A., Dréno B., Larkin J., Ribas A., Liszkay G., Maio M. et al. (eds.). 5­year survival update of cobimetinib plus vemurafenib BRAF V600 mutationpositive advanced melanoma: final analysis of the coBRIM study. 16th International Congress of the Society for Melanoma Research. Salt Lake City, UT, USA. 2019 November 20-23.
  34. Ribas A., Daud A., Pavlick A.C., Gonzalez R., Lewis K.D., Hamid O. et al. Extended 5-Year Follow-up Results of a Phase Ib Study (BRIM7) of Vemurafenib and Cobimetinib in BRAF-Mutant Melanoma. Clin Cancer Res. 2020;26(1):46-53. https://doi.org/10.1158/1078-0432.CCR-18-4180.
  35. Das Thakur M., Salangsang F., Landman A.S., Sellers W.R., Pryer N.K., Levesque M.P. et al. Modelling vemurafenib resistance in melanoma reveals a strategy to forestall drug resistance. Nature. 2013;494(7436):251-255. https://doi.org/10.1038/nature11814.
  36. Dooley A.J., Gupta A., Bhattacharyya M., Middleton M.R. Intermittent dosing with vemurafenib in BRAF V600E-mutant melanoma: review of a case series. Ther Adv Med Oncol. 2014;6(6):262-266. https://doi.org/10.1177/1758834014548187.
  37. Algazi A., Othus M., Daud A., Lo R., Mehnert J., Truong T.-G. et al. (eds.). SWOG S1320: Improved progression­free survival with continuous compared to intermittent dosing with dabrafenib and trametinib in patients with BRAF mutated melanoma. AACR Annual Meeting 2020. 2020 April 27. Virtual Meeting I.
  38. Ascierto P.A., Ferrucci P.F., Stephens R., Del Vecchio M., Atkinson V., Schmidt H. et al. Keynote-022 part 3: phase 2 randomized study of 1l dabrafenib (d) and trametinib (t) plus pembrolizumab (pembro) or placebo (pbo) for BRAF-mutant advanced melanoma. Ann Oncol. 2018;29:442-466. https://doi.org/10.1093/annonc/mdy289.
  39. McArthur G., Stroyakovskiy D., Gogas H., Robert C., Lewis K., Protsenko S. et al. (eds.). Evaluation of atezolizumab (A), cobimetinib (C), and vemurafenib (V) in previously untreated patients with BRAFV600 mutation­positive advanced melanoma: Primary results from the phase 3 IMspire150 trial. AACR Annual Meeting 2020. 2020 April 27. Virtual Annual Meeting I.
  40. Kreft S., Gesierich A., Eigentler T., Franklin C., Valpione S., Ugurel S. et al. Efficacy of PD-1-based immunotherapy after radiologic progression on targeted therapy in stage IV melanoma. Eur J Cancer. 2019;116:207-215. https://doi.org/10.1016/j.ejca.2019.05.015.
  41. Самойленко И.В., Жуликов Я.А., Харкевич Г.Ю., Петенко Н.Н., Демидов Л.В. Опыт применения ниволумаба в терапии предлеченных пациентов с метастатической меланомой кожи. Злокачественные опухоли. 2018;8(3):78-85. https://doi.org/10.18027/2224-5057-2018-8-3-78-85.
  42. Johnson D.B., Pectasides E., Feld E., Ye F., Zhao S., Johnpulle R. et al. Sequencing Treatment in BRAFV600 Mutant Melanoma: Anti-PD-1 Before and After BRAF Inhibition. J Immunother. 2017;40(1):31-35. https://doi.org/10.1097/CJI.0000000000000148.
  43. Samoylenko I., Kharkevich G., Petenko N.N., Orlova K.V., Sinelnikov I., Utyashev I.A. et al. Paclitaxel and carboplatin chemotherapy in patients with metaststic melanoma refractory to BRAF/MEK inhibitors. Journal of Clinical Oncology. 2016;34(15):9552. https://doi.org/10.1200/JCO.2016.34.15_suppl.9552.
  44. Valpione S., Carlino M.S., Mangana J., Mooradian M.J., McArthur G., Schadendorf D. et al. Rechallenge with BRAF-directed treatment in metastatic melanoma: A multi-institutional retrospective study. Eur J Cancer. 2018;91:116-124. https://doi.org/10.1016/j.ejca.2017.12.007.
  45. Schreuer M., Jansen Y., Planken S., Chevolet I., Seremet T., Kruse V. et al. Combination of dabrafenib plus trametinib for BRAF and MEK inhibitor pretreated patients with advanced BRAF(V600)-mutant melanoma: an open-label, single arm, dual-centre, phase 2 clinical trial. Lancet Oncol. 2017;18(4):464-472. https://doi.org/10.1016/S1470-2045(17)30171-7.
  46. Amann V.C., Hoffmann D., Mangana J., Dummer R., Goldinger S.M. Successful retreatment with combined BRAF/MEK inhibition in metastatic BRAFV600-mutated melanoma. J Eur Acad Dermatol Venereol. 2017;31(10):1638-1640. https://doi.org/10.1111/jdv.14268.
  47. Самойленко И.В., Жуликов Я.А., Демидов Л.В. Повторное применение ингибиторов BRAF и MEK у больных метастатической меланомой после прогрессирования на ингибиторах BRAF и МЕК. Обзор литературы и клиническое наблюдение. Медицинский совет. 2017;14(6):6-10. https://doi.org/10.21518/2079-701X-2017-14-6-10.
  48. Desvignes C., Abi Rached H., Templier C., Drumez E., Lepesant P., Desmedt E. et al. BRAF inhibitor discontinuation and rechallenge in advanced melanoma patients with a complete initial treatment response. Melanoma Res. 2017;27(3):281-287. https://doi.org/10.1097/CMR.0000000000000350.
  49. Carlino M.S., Vanella V., Girgis C., Giannarelli D., Guminski A., Festino L. et al. Cessation of targeted therapy after a complete response in BRAF-mutant advanced melanoma: a case series. Br J Cancer. 2016;115(11):1280-1284. https://doi.org/10.1038/bjc.2016.321.
  50. Vanhaecke C., Deilhes F., Chanal J., Regnier-Rosencher E., Boitier F., Boulinguez S. et al. BRAF V600 inhibitor discontinuation after complete response in advanced melanoma: a retrospective analysis of 16 patients. Br J Dermatol. 2017;177(4):94-95. https://doi.org/10.1111/bjd.15345.
  51. Reschke R., Simon J.C., Ziemer M. Rechallenge of targeted therapy in metastatic melanoma. J Dtsch Dermatol Ges. 2019;17(5):483-486. https://doi.org/10.1111/ddg.13766.
  52. Vinal D., Martinez D., Espinosa E. Efficacy of rechallenge with BRAF inhibition therapy in patients with advanced BRAFV600 mutant melanoma. Clin Transl Oncol. 2019;21(8):1061-1066. https://doi.org/10.1007/s12094-018-02028-0.
  53. Simonaggio A., Michot J.M., Voisin A.L., Le Pavec J., Collins M., Lallart A. et al. Evaluation of Readministration of Immune Checkpoint Inhibitors After Immune-Related Adverse Events in Patients With Cancer. JAMA Oncol. 2019. https://doi.org/10.1001/jamaoncol.2019.1022.
  54. Reschke R., Ziemer M. Rechallenge with checkpoint inhibitors in metastatic melanoma. J Dtsch Dermatol Ges. 2020;18(5):429-436. https://doi.org/10.1111/ddg.14091.
  55. Tedbirt B., De Pontville M., Branger P., Picard C., Baroudjian B., Lebbe C. et al. Rechallenge of immune checkpoint inhibitor after pembrolizumabinduced myasthenia gravis. Eur J Cancer. 2019;113:72-74. https://doi.org/10.1016/j.ejca.2019.03.006.


Журнал