Activity of trametinib in K601E and L597Q BRAF mutation-positive metastatic melanoma

Abstract

BRAF and MEK inhibitors are not established treatments for non-V600 mutation-positive metastatic melanoma. We carried out a retrospective analysis of efficacy and safety in four patients with BRAF K601E and one patient with L597Q mutation-positive metastatic melanoma treated with the MEK inhibitor trametinib. Three patients achieved a RECIST partial response, including the patient with an L597Q mutation. Paired biopsies available in one of the five patients showed reduced phospho-ERK signalling and this corresponded to a metabolic response on F-fluorodeoxyglucose-PET scanning. Trametinib toxicity was manageable. Trametinib has antitumour activity in patients with BRAF K601E and L597Q mutation-positive metastatic melanoma.

Targeted agents and immunotherapies: optimizing outcomes in melanoma

“…An additional 3-5% of melanomas harbour other forms of genetic alteration in BRAF that are also considered to be oncogenic 5 . These aberrations are divided between missense mutations in the region adjacent to V600 (within exon 15) or distant from this site (within exon 11), and BRAF translocations (also referred to as fusions) [25][26][27][28] . In melanomas and other cancers, dozens of sites in BRAF exons 11 and 15 have been found to harbour missense mutations, but only a small number have been functionally characterized.…”

“…BRAF translocations generate proteins in which the kinase domain of BRAF is fused with regulatory domains of vari ous other proteins 27 . Preclinical evidence indicates that the currently available BRAF inhibitors do not inhibit these non-V600-mutant forms of BRAF, nor BRAF fusion proteins 27,32 ; however, MEK inhibitors are effective in suppressing signalling downstream of these BRAF mutants in experimental systems, and anecdotal reports of patients with such alterations responding to MEK inhibitors have been published [26][27][28] .…”

“…Responses to MEK inhibitors have also been observed in patients with tumours harbouring non-V600 BRAF mutations, or a BRAF/NRAS-wild-type status [26][27][28] ; however, the numbers of patients included were small, limiting comparisons between the outcomes of these groups and those observed with MEK-inhibitor monotherapy in BRAF-V600-mutant and NRAS-mutant populations. Nevertheless, the current evidence in NRAS-mutant melanoma indicates that investi gation of MEK-inhibitor-based combination regimens seems justified.…”

Genomically Driven Tumors and Actionability across Histologies:BRAF-Mutant Cancers as a Paradigm

“…Again, it is plausible that the brain is a sanctuary in this patient, and that resistance may not be due to insensitivity to the drug. Similarly, a melanoma patient with the BRAF L597Q aberration had disease progression within 2 months of treatment with a BRAF inhibitor (67), but another melanoma patient with this aberration had a partial response to treatment with trametinib (68). Finally, a BRAF L597S-positive melanoma patient was reported to derive clinical benefit after treatment with the MEK inhibitor, TAK-733 (69).…”

Mitogen-Activated Protein Kinase Signaling Pathway in Cutaneous Melanoma: An Updated Review

“…12 Moreover, these agents have also shown a beneficial therapeutic effect in patients with BRAF-mutant melanoma that do not respond to BRAF inhibitors. 29 A potential benefit of combining MEK1/MEK2 and BRAF inhibitors has been suggested by preclinical studies that showed a rapid MEK-dependent recovery of MAPK pathway signaling after BRAF inhibitor monotherapy. 12,21 In fact, combined BRAF-MEK1/MEK2 inhibition has already demonstrated benefits over single-agent therapy in phase III clinical trials, and a combined drug regimen is likely to become the standard of care for BRAF-mutant metastatic melanoma in the near future.…”