Reference Detail

Ref Type

Journal Article

PMID

(33861486)

Authors

Nebhan CA, Johnson DB, Sullivan RJ, Amaria RN, Flaherty KT, Sosman JA, Davies MA

Title

Efficacy and Safety of Trametinib in Non-V600 BRAF Mutant Melanoma: A Phase II Study.

Journal	Vol	Issue	Date	Pages	Journal Short Title
The oncologist	26	9	2021 09	731-e1498	Oncologist

URL

Abstract Text

This study suggests that trametinib has significant clinical activity in non-V600 BRAF mutation and BRAF fusion metastatic melanoma, albeit in a small cohort. All patients with metastatic melanoma should undergo sequencing of the BRAF gene to identify noncanonical BRAF mutations that may indicate benefit from treatment with trametinib.Non-V600 BRAF mutations and BRAF fusions in aggregate occur in approximately 5% of all melanomas. Inhibition of the mitogen-activated protein kinase (MAPK) pathway has been implicated as a possible treatment strategy for these patients.In this open-label, multicenter, phase II study, patients with advanced melanoma harboring mutations in BRAF outside V600 (non-V600) or BRAF fusions received trametinib 2.0 mg daily. Patients were divided into cohorts based on the intrinsic catalytic activity of BRAF mutation (high, cohort A; low/unknown, cohort B). The primary endpoint was objective response rate (ORR) for patients in cohort A; secondary endpoints included ORR in cohort B, safety, and survival in both treatment arms.Among all patients, the ORR was 33% (three of nine patients), including 67% in cohort A and 17% in cohort B. Two patients had stable disease as best response, and six patients had some degree of tumor shrinkage. The median progression-free survival (PFS) was 7.3 months. Treatment-related adverse events occurred in all patients (100%); most (89%) were grade 1-2.In contrast to recently described tumor-agnostic studies in a genetically similar population, trametinib had considerable activity in a small population of patients with melanoma harboring BRAF non-V600 mutations and fusions, providing rationale for sequencing in search of these genomic alterations.

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Molecular Profile	Treatment Approach

Gene Name	Source	Synonyms	Protein Domains	Gene Description	Gene Role

Therapy Name	Drugs	Efficacy Evidence	Clinical Trials

Drug Name	Trade Name	Synonyms	Drug Classes	Drug Description

Gene	Variant	Impact	Protein Effect	Variant Description	Associated with drug Resistance
BRAF	T470R	missense	unknown	BRAF T470R lies within the protein kinase domain of the Braf protein (UniProt.org). T470R has been identified in the scientific literature (PMID: 33861486), but has not been biochemically characterized and therefore, its effect on Braf protein function is unknown (PubMed, Sep 2024).

Molecular Profile	Indication/Tumor Type	Response Type	Therapy Name	Approval Status	Evidence Type	Efficacy Evidence	References
BRAF A598_T599insV	melanoma	predicted - sensitive	Trametinib	Case Reports/Case Series	Actionable	In a Phase II trial, Mekinist (trametinib) treatment resulted in clinical benefit in six of nine melanoma patients harboring BRAF fusions or non-V600 BRAF mutations, including stable disease lasting 7.3 months with a tumor reduction of 8% in a patient harboring BRAF A598_T599insV, who also harbored KIT M541L (PMID: 33861486; NCT02296112).	33861486
BRAF L597Q	melanoma	predicted - sensitive	Trametinib	Case Reports/Case Series	Actionable	In a Phase II trial, Mekinist (trametinib) treatment resulted in an objective response rate of 33% (3/9, all partial responses) and a median progression-free survival (PFS) of 7.3 months in melanoma patients harboring BRAF fusions or non-V600 BRAF mutations, including a partial response with a tumor reduction of 38% and PFS ongoing 8.3 months in a patient harboring BRAF L597Q (PMID: 33861486; NCT02296112).	33861486
BRAF T470R	melanoma	predicted - sensitive	Trametinib	Case Reports/Case Series	Actionable	In a Phase II trial, Mekinist (trametinib) treatment resulted in an objective response rate of 33% (3/9, all partial responses) and a median progression-free survival (PFS) of 7.3 months in melanoma patients harboring BRAF fusions or non-V600 BRAF mutations, including a partial response with a tumor reduction of 87% and a PFS of 19.3 months in a patient harboring BRAF T470R (PMID: 33861486; NCT02296112).	33861486