BRAF/MEK Inhibitors Effective in Patient With Rare Melanoma Mutation

BRAF and MEK inhibitors are likely to be effective against patients with melanoma who carry the orphan p.V600_K601delinsE mutation, although patient safety ought to be carefully monitored, according to a case report.

Investigators at the University Hospital of Tours, in France, wrote about their experience with a 46-year-old man with stage IV melanoma who was given BRAF and MEK inhibitors (BRAFi/MEKi) in a case report published in the International Journal of Dermatology.

Corresponding author Jordane Barbé, MD, and colleagues wrote that mutations in the BRAF gene, which are found in about half of cutaneous melanomas, are most often found at exon 15 codon 600, which results in consecutive BRAF-mediated activation of the mitogen-activated protein kinase (MAPK) pathway.

BRAFi/MEKi have been approved to treat metastatic melanomas with activating BRAF p.V600E or p.V600K mutations, and have been shown to be effective in other activating mutations along codon 600. Yet, the investigators noted that there is so far little evidence regarding the therapies’ efficacy in “orphan” non-p.V600E/K/R/D mutations.

In the report, the investigators outlined their treatment of a patient with a metastatic melanoma with a mutation combining the deletion of the valine (V) at position 600, the deletion of the lysine (K) at position 601, and the insertion of a glutamic acid (E). The patient had a stage IV melanoma with inguinal and iliac lymph nodes, liver, and skin metastases.

“High Resolution Melting for rapid screening on the primary melanoma was consistent with a mutation of the BRAF gene in exon 15, but pyrosequencing did not detect mutations in codon 600,” Barb and colleagues wrote. “Sanger sequencing of BRAF exon 15 on both primary and skin metastasis revealed a p.V600_K601delinsE variant of uncertain significance.”

At first, the patient was given ipilimumab (Yervoy) 3 mg/kg and nivolumab (Opdivo) 1 mg/kg. The patient experienced a partial response, but the therapy had to be stopped after 3 courses due to grade 3 rhabdomyolysis, they said.

The patient continued on nivolumab but after 9 months, progression of iliac and inguinal lymph nodes was identified; it was confirmed 3 months later.

At that point, the investigators switched to dabrafenib (Tafinlar) and trametinib (Mekinist), which sparked regression of inguinal and iliac lymph nodes by 4 weeks. After 4 months, grade 3 cytolytic hepatitis forced clinicians to switch to vemurafenib/cobimetinib (Zelboraf)/Cotellic). Within 3 months, surgeons were able to remove the single remaining detectable lymph node.

“Histology later confirmed the persistence of tumoral cells carrying the p.V600_K601delinsE mutation in the BRAF gene,” the investigators wrote. “Meanwhile the patient had blurred vision related to serious grade 2 chorioretinopathy, leading to withdrawal of BRAFi/MEKi.”

Reintroduction of systemic therapy was deemed unnecessary and the patient was still free of disease following 20 months’ follow-up, the investigators said.

The authors concluded that while it was possible that the patient’s improvement was a delayed response to immunotherapy, they believe the balance of evidence suggests it was the BRAFi/MEKi that caused the improvement. Similarly, they said it was not certain whether the toxicities experienced by the patient had to do with his underlying rare mutation or other factors.

They said such toxicities mean patients with similar orphan mutations should be watched closely for toxicities, but also said their evidence supports the potential efficacy of BRAFi/MEKi in such patients.

Reference

Barbé J, Garnier M, Tallet A, et al. Efficacy and tolerance of BRAF and MEK inhibitors on metastatic melanoma carrying the orphan pV600_K601 delinsE mutation of the BRAF gene. Int J Dermatol. Published online March 18, 2021. doi:10.1111/ijd.15538