Efficacy of Vemurafenib in a Trametinib-Resistant Stage IV Melanoma Patient—Letter

Targeted treatment of BRAF gene–mutated melanoma with BRAF and MEK inhibitors has prolonged progression-free and overall survival (1, 2). Several mechanisms of resistance to BRAF and MEK inhibition treatment have been described, most of which involve reactivation of downstream MAP–ERK kinase/extracellular signal–regulated kinase (MEK/ERK) signaling (3). Thus, BRAF-inhibitor resistance mechanisms would be expected to confer resistance to downstream MEK inhibitor (4). The outcome of an upstream inhibition of the signaling pathway is elusive in which an MEK inhibitor is followed by a BRAF inhibitor (5).

Here, we report on a 43-year-old male Caucasian patient with BRAF V600E–mutated stage IV melanoma who was treated successfully for 10 months with the MEK inhibitor trametinib. Under this treatment, metastases in lung, lymph nodes, and subcutaneous tissue were regressive. However, tumor cells became resistant indicated by fast progressive disease with new brain and dedifferentiated subcutaneous metastases (Fig. 1A). A cell line established from trametinib-resistant melanoma cells (Fig. 1B) showed high levels of ERK and perk, suggesting still a strong activity of the BRAF/MEK/ERK signaling pathway (Fig. 1C). We could not detect mutations in the coding sequence of MEK1 (MEK2 was not transcriptionally expressed) that may inhibit the binding-site of trametinib and thus might explain the activation of the pathway. To exclude amplification of gene copy numbers of genes involved in the BRAF/MEK/ERK signaling pathway resulting in a higher transcriptional activity, we performed FISH experiments with gene locus-specific probes (Fig. 1D and Supplementary Table S1). However, no amplification of these gene loci in trametinib-resistant cells could be seen, suggesting other transcriptional mechanisms explaining the trametinib resistance.

In search for a potential treatment option for our patient, we tested viable melanoma cells (Fig. 1B) in vitro for potential targeted therapies. We could detect still a strong inhibition of cell growth and pERK levels with the BRAF inhibitor vemurafenib (Fig. 1E and F). This prompted us to treat our patient with vemurafenib 480 mg twice per day. One week after induction of vemurafenib treatment, the symptoms of the patient ameliorated (ECOG2 improved to ECOG0) and tumor masses regressed (Supplementary Fig. S1). Unfortunately, treatment with vemurafenib had to be interrupted after 1 month due to grade 3 tachycardia and heart toxicity and the patient died 2 months later.

This case shows that upstream sequential treatment with a BRAF-inhibitor might be still efficient in MEK inhibitor–resistant patients with melanoma. Besides the sequential administration shown here, intermittent administration also should be studied further.