Successful treatment of MAP2K1 mutant stage IV-M1d melanoma with trametinib plus low-dose dabrafenib: a case report

Front Med (Lausanne). 2024 Sep 9:11:1436774. doi: 10.3389/fmed.2024.1436774. eCollection 2024.

Abstract

Clonal MAPK-pathway activating mutations in the MAP2K1 (MEK1) gene are present in approximately 9% of cutaneous melanomas. These mutations are divided into three classes: RAF-dependent, RAF-regulated, RAF-independent. Cell lines with class-2 or RAF-regulated MAP2K1-mutations are most responsive to MEK-inhibitors. We present a patient with a class-2 MAP2K1-mutant stage IV-M1d melanoma who experienced extra- and intracranial progressive disease following treatment with immune-checkpoint inhibitors. The patient was treated with the MEK-inhibitor trametinib (2 mg OD) to which a low-dose of dabrafenib (50 mg BID) was added to mitigate skin-toxicity. Following documentation of a partial response (PR), she developed one new, and increase in volume of two pre-existing brain metastases that were treated with stereotactic radiosurgery (SRS) while continuing trametinib and dabrafenib. Thereafter, a deep partial radiologic and metabolic response both extra-and intra-cranially was achieved and is ongoing 88 weeks after initiating trametinib. She experienced no grade > 2 adverse events. Focal post-radiation necrosis at site of an irradiated brain metastasis developed 9 months after SRS and is successfully being treated with low-dose bevacizumab. This is the first published case of a durable intracranial disease control with the MEK-inhibitor trametinib of a stage IV-M1d class-2 MAP2K1-mutant melanoma. This illustrates the utility of NGS profiles that include class-1/2 MAP2K1-mutations in patients with melanoma and other malignancies to provide valuable information on a potentially active individualized treatment option. A prospective clinical trial that further evaluates the efficacy of MEK-inhibitor therapies in MAP2K1-mutated tumors is justified.

Keywords: MAP2K1-mutation; MEK-inhibitor; MEK1-mutation; brain metastasis; case report; focal post-radiation necrosis; stage IV melanoma; trametinib.

Publication types

  • Case Reports

Grants and funding

The authors declare that financial support was received for the research of this article. Research funding from Novartis was received for the trial in which the patient was included (NCT04059224). The funder was not involved in the study design, collection, analysis, interpretation of data, the writing of this article, or the decision to submit it for publication.