Повторное применение ингибиторов BRAF и MEK при лечении метастатической меланомы: клинический случай и мини-обзор

Лечение пациентов с метастатической меланомой по-прежнему представляет собой сложную клиническую задачу. Реальная практика лечения пациента энкорафенибом и биниметинибом после прогрессирования на комбинированной иммунотерапии  и комбинированной таргетной терапии демонстрирует хорошую переносимость и достижение контроля над болезнью, в том числе в ЦНС. У пациента после прогрессирования на фоне химиотерапии, комбинированной таргетной терапии, комбинированной иммунотерапии развилось распространенное поражение оболочек головного и спинного мозга, пациент испытывал неврологические симптомы (головную боль, боль в шее, боль в спине, судорожные припадки). Повторное назначение ингибиторов BRAFi + MEKi с переключением на лекарственные препараты нового поколения позволило добиться контроля над заболеванием, регресса неврологической симптоматики и хорошего качества жизни на протяжении более 12 мес. Данный клинический случай демонстрирует потенциальную эффективность повторного применения комбинированной таргетной терапии с переключением на препараты более нового класса, что может позволить добиться контроля над заболеванием в течение длительного времени и обеспечить пациенту хорошее качество жизни. В публикации также приводится обсуждение возможных стратегий ведения пациентов после прогрессирования на ингибиторах BRAFi + MEKi, доступных в настоящее время.

1. Tietze JK, Forschner A, Loquai C, Mitzel-Rink H, Zimmer L, Meiss F et al. The efficacy of re-challenge with BRAF inhibitors after previous progression to BRAF inhibitors in melanoma: A retrospective multicenter study. Oncotarget. 2018;9(76):34336–34346. https://doi.org/10.18632/oncotarget.26149.

2. Valpione S, Carlino MS, Mangana J, Mooradian MJ, 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.

3. Amann VC, Hoffmann D, Mangana J, Dummer R, Goldinger SM. Successful retreatment with combined BRAF/MEK inhibition in metastatic BRAFV600mutated melanoma. J Eur Acad Dermatol Venereol. 2017;31(10):1638–1640. https://doi.org/10.1111/jdv.14268.

4. Van Not OJ, van den Eertwegh AJM, Haanen JB, van Rijn RS, Aarts MJB, van den Berkmortel F et al. BRAF/MEK inhibitor rechallenge in advanced melanoma patients. Cancer. 2024;130(9):1673–1683. https://doi.org/10.1002/cncr.35178.

5. Haist M, Stege H, Rogall F, Tan Y, von Wasielewski I, Klespe KC et al. Treatment management for BRAF-mutant melanoma patients with tumor recurrence on adjuvant therapy: a multicenter study from the prospective skin cancer registry ADOREG. J Immunother Cancer. 2023;11(9):е007630. https://doi.org/10.1136/jitc-2023-007630.

6. Schreuer M, Jansen Y, Planken S, Chevolet I, Seremet T, Kruse V, Neyns B. 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.

7. Hartman ML, Koziej P, Kluszczynska K, Czyz M. Pro-Apoptotic Activity of MCL-1 Inhibitor in Trametinib-Resistant Melanoma Cells Depends on Their Phenotypes and Is Modulated by Reversible Alterations Induced by Trametinib Withdrawal. Cancers. 2023;15(19):4799. https://doi.org/10.3390/cancers15194799.

8. Priantti JN, Vilbert M, Madeira T, Moraes FCA, Hein ECK, Saeed A, Cavalcante L. Efficacy and Safety of Rechallenge with BRAF/MEK Inhibitors in Advanced Melanoma Patients: A Systematic Review and Meta-Analysis. Cancers. 2023;15(15):3754. https://doi.org/10.3390/cancers15153754.

9. Mu Y, Hao X, Yang K, Ma D, Wang S, Xu Z, Li J, Xing P. Clinical Modality of Resistance and Subsequent Management of Patients with Advanced Non-small Cell Lung Cancer Failing Treatment with Osimertinib. Target Oncol. 2019;14(3):335–342. https://doi.org/10.1007/s11523-019-00644-6.

10. Ascierto PA, Casula M, Bulgarelli J, Pisano M, Piccinini C, Piccin L et al. Sequential immunotherapy and targeted therapy for metastatic BRAF V600 mutated melanoma: 4-year survival and biomarkers evaluation from the phase II SECOMBIT trial. Nat Commun. 2024;15(1):146. https://doi.org/10.1038/s41467-023-44475-6.

11. Atkins MB, Lee SJ, Chmielowski B, Tarhini AA, Cohen GI, Truong TG et al. Combination Dabrafenib and Trametinib Versus Combination Nivolumab and Ipilimumab for Patients With Advanced BRAF-Mutant Melanoma: The DREAMseq Trial-ECOG-ACRIN EA6134. J Clin Oncol. 2023;41(2):186–197. https://doi.org/10.1200/JCO.22.01763.

12. Zimmer L, Dimitriou F, Grover P, Hassel JC, Erdmann M, Forschner A et al. Anti-PD1 plus BRAF/MEK inhibitors (triplet therapy) after failure of standard therapy in patients (pts) with advanced melanoma. J Clin Oncol. 2023;41:9528–9528. https://doi.org/10.1200/JCO.2023.41.16_suppl.9528.

13. Samoylenko I, Kolonotareva Yu, Kogay E, Zhukova N, Utyashev I, Ivannikov M et al. Triple combination of vemurafenib, cobimetinib and atezolizumab in real clinical practice in Russian Federation: results of the A1 cohort of the ISABELLA study. Front Oncol. 2024;14:1395378. https://doi.org/10.3389/fonc.2024.1395378.

14. Awada G, Schwarze JK, Tijtgat J, Fasolino G, Kruse V, Neyns B. A lead-in safety study followed by a phase 2 clinical trial of dabrafenib, trametinib and hydroxychloroquine in advanced BRAFV600 mutant melanoma patients previously treated with BRAF-/MEK-inhibitors and immune checkpoint inhibitors. Melanoma Res. 2022;32(3):183–191. https://doi.org/10.1097/CMR.0000000000000821.

15. Samoylenko I, Kharkevich G, Petenko NN, Orlova KV, Sinelnikov I, Utyashev IA et al. Paclitaxel and carboplatin chemotherapy in patients with metaststic melanoma refractory to BRAF/MEK inhibitors. J Clin Oncol. 2016;34(15):9552–9552. https://doi.org/10.1200/JCO.2016.34.15_suppl.9552.

16. Glaviano A, Foo ASC, Lam HY, Yap KCH, Jacot W, Jones RH et al. PI3K/AKT/ mTOR signaling transduction pathway and targeted therapies in cancer. Mol Cancer. 2023;22(1):138. https://doi.org/10.1186/s12943-023-01827-6.

17. White MG, Szczepaniak Sloane R, Witt RG, Reuben A, Gaudreau PO, Andrews MC et al. Short-term treatment with multi-drug regimens combining BRAF/MEK-targeted therapy and immunotherapy results in durable responses in Braf-mutated melanoma. Oncoimmunology. 2021;10(1):1992880. https://doi.org/10.1080/2162402X.2021.1992880.

18. Gao MZ, Wang HB, Chen XL, Cao WT, Fu L, Li Y et al. Aberrant modulation of ribosomal protein S6 phosphorylation confers acquired resistance to MAPK pathway inhibitors in BRAF-mutant melanoma. Acta Pharmacol Sin. 2019;40(2):268–278. https://doi.org/10.1038/s41401-018-0020-z.

19. Soumoy L, Schepkens C, Krayem M, Najem A, Tagliatti V, Ghanem GE et al. Metabolic Reprogramming in Metastatic Melanoma with Acquired Resistance to Targeted Therapies: Integrative Metabolomic and Proteomic Analysis. Cancers. 2020;12(5):1323. https://doi.org/10.3390/cancers12051323.

20. Salzmann M, Wald A, Stege H, Loquai C, Zimmer L, Hayani KM et al. Tolerability of BRAF and MEK Inhibitors for Metastasized Melanoma after Intra-Class Switch: A Multicenter, Retrospective Study. Cancers. 2023;15(5):1426. https://doi.org/10.3390/cancers15051426.

21. Rodriguez CI, Castro-Perez E, Prabhakar K, Block L, Longley BJ, Wisinski JA et al. EPAC-RAP1 Axis-Mediated Switch in the Response of Primary and Metastatic Melanoma to Cyclic AMP. Mol Cancer Res. 2017;15(12):1792–1802. https://doi.org/10.1158/1541-7786.MCR-17-0067.

22. Falchook GS, Long GV, Kurzrock R, Kim KB, Arkenau TH, Brown MP et al. Dabrafenib in patients with melanoma, untreated brain metastases, and other solid tumours: a phase 1 dose-escalation trial. Lancet. 2012;379(9829):1893–1901. https://doi.org/10.1016/S0140-6736(12)60398-5.

23. Infante JR, Fecher LA, Falchook GS, Nallapareddy S, Gordon MS, Becerra C et al. Safety, pharmacokinetic, pharmacodynamic, and efficacy data for the oral MEK inhibitor trametinib: a phase 1 dose-escalation trial. Lancet Oncol. 2012;13(8):773–781. https://doi.org/10.1016/S1470-X