Rechallenge with BRAF and MEK inhibitors in the treatment of metastatic melanoma: A case report with a mini-review

The management of patients with metastatic melanoma remains a difficult clinical problem. Real-world practice of treating patients with encorafenib and binimetinib after progression on combination immunotherapy and combination targeted therapy demonstrates good tolerability and achievements in disease control, including the central nervous system. After progression on chemotherapy, combination targeted therapy, and combination immunotherapy, the patient developed extensive brain and spinal cord lesions and suffered from neurological symptoms (headache, neck pain, back pain, seizures). Rechallenge with BRAFi+MEKi inhibitors and switching to new generation drugs allowed us to achieve disease control, regression of neurological symptoms and a good quality of life for more than 12 months. This clinical case demonstrates the potential efficacy of rechallenge with combination targeted therapy and switching to newer class drugs, which helps achieve a long-term disease control and improve the patient’s quality of life. The article also provides a discussion of possible management strategies for patients who have progressed on currently available BRAFi + MEKi inhibitors.

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