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Ref Type

Journal Article

PMID

(38479118)

Authors

Wei X, Zou Z, Zhang W, Fang M, Zhang X, Luo Z, Chen J, Huang G, Zhang P, Cheng Y, Liu J, Liu J, Zhang J, Wu D, Chen Y, Ma X, Pan H, Jiang R, Liu X, Ren X, Tian H, Jia Z, Guo J, Si L

Title

A phase II study of efficacy and safety of the MEK inhibitor tunlametinib in patients with advanced NRAS-mutant melanoma.

Journal	Vol	Issue	Date	Pages	Journal Short Title
European journal of cancer (Oxford, England : 1990)	202		2024 Mar 11	114008	Eur J Cancer

URL

Abstract Text

NRAS-mutant melanoma is an aggressive subtype with poor prognosis; however, there is no approved targeted therapy to date worldwide.We conducted a multicenter, single-arm, phase II, pivotal registrational study that evaluated the efficacy and safety of the MEK inhibitor tunlametinib in patients with unresectable, stage III/IV, NRAS-mutant melanoma (NCT05217303). The primary endpoint was objective response rate (ORR) assessed by independent radiological review committee (IRRC) per Response Evaluation Criteria in Solid Tumors (RECIST) v1.1. The secondary endpoints included progression-free survival (PFS), disease control rate (DCR), duration of response(DOR), overall survival (OS) and safety.Between November 2, 2020 and February 11, 2022, a total of 100 patients were enrolled. All (n = 100) patients received at least one dose of tunlametinib (safety analysis set [SAS]) and 95 had central laboratory-confirmed NRAS mutations (full analysis set [FAS]). In the FAS, NRAS mutations were observed at Q61 (78.9%), G12 (15.8%) and G13 (5.3%). The IRRC-assessed ORR was 35.8%, with a median DOR of 6.1 months. The median PFS was 4.2 months, DCR was 72.6% and median OS was 13.7 months. Subgroup analysis showed that in patients who had previously received immunotherapy, the ORR was 40.6%. No treatment-related deaths occurred.Tunlametinib showed promising antitumor activity with a manageable safety profile in patients with advanced NRAS-mutant melanoma, including those who had prior exposure to immunotherapy. The findings warrant further validation in a randomized clinical trial.

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Molecular Profile	Indication/Tumor Type	Response Type	Therapy Name	Approval Status	Evidence Type	Efficacy Evidence	References
NRAS act mut	melanoma	predicted - sensitive	Tunlametinib	Phase II	Actionable	In a Phase II trial, Tunlametinib (HL-085) treatment demonstrated safety and activity in Chinese patients with advanced melanoma harboring NRAS mutations (including mutations at Q61, G12, and G13), with an objective response rate of 35.8% (34/95, all partial responses), a median progression-free survival of 4.2 months, disease control rate of 72.6% (69/95), median duration of response of 6.1 months, and median overall survival of 13.7 months (PMID: 38479118; NCT05217303).	38479118
NRAS G12X	melanoma	predicted - sensitive	Tunlametinib	Phase II	Actionable	In a Phase II trial, Tunlametinib (HL-085) treatment resulted in a confirmed objective response rate (ORR) of 35.8% (34/95, all partial responses), a median progression-free survival of 4.2 months, disease control rate of 72.6% (69/95), median duration of response of 6.1 months, and median overall survival of 13.7 months in Chinese patients with advanced melanoma harboring NRAS mutations, with an ORR of 13.3% in patients with an NRAS G12 mutation (n=15) (PMID: 38479118; NCT05217303).	38479118
NRAS Q61X	melanoma	predicted - sensitive	Tunlametinib	Phase II	Actionable	In a Phase II trial, Tunlametinib (HL-085) treatment resulted in a confirmed objective response rate (ORR) of 35.8% (34/95, all partial responses), a median progression-free survival of 4.2 months, disease control rate of 72.6% (69/95), median duration of response of 6.1 months, and median overall survival of 13.7 months in Chinese patients with advanced melanoma harboring NRAS mutations, with an ORR of 41.3% in patients with an NRAS Q61 mutation (n=75) (PMID: 38479118; NCT05217303).	38479118
NRAS G12D	melanoma	predicted - sensitive	Tunlametinib	Case Reports/Case Series	Actionable	In a Phase II trial, Tunlametinib (HL-085) treatment resulted in a confirmed objective response rate of 35.8% (34/95, all partial responses), a median progression-free survival of 4.2 months, disease control rate of 72.6% (69/95), median duration of response of 6.1 months, and median overall survival of 13.7 months in Chinese patients with advanced melanoma harboring NRAS mutations including NRAS Q61R (40%), Q61K (29.5%), and G12D (9.5%) (PMID: 38479118; NCT05217303).	38479118
NRAS G13X	melanoma	predicted - sensitive	Tunlametinib	Case Reports/Case Series	Actionable	In a Phase II trial, Tunlametinib (HL-085) treatment resulted in a confirmed objective response rate (ORR) of 35.8% (34/95, all partial responses), a median progression-free survival of 4.2 months, disease control rate of 72.6% (69/95), median duration of response of 6.1 months, and median overall survival of 13.7 months in Chinese patients with advanced melanoma harboring NRAS mutations, with an ORR of 13.3% in patients with an NRAS G13 mutation (n=5) (PMID: 38479118; NCT05217303).	38479118
NRAS Q61K	melanoma	predicted - sensitive	Tunlametinib	Case Reports/Case Series	Actionable	In a Phase II trial, Tunlametinib (HL-085) treatment resulted in a confirmed objective response rate of 35.8% (34/95, all partial responses), a median progression-free survival of 4.2 months, disease control rate of 72.6% (69/95), median duration of response of 6.1 months, and median overall survival of 13.7 months in Chinese patients with advanced melanoma harboring NRAS mutations including NRAS Q61R (40%), Q61K (29.5%), and G12D (9.5%) (PMID: 38479118; NCT05217303).	38479118
NRAS Q61R	melanoma	predicted - sensitive	Tunlametinib	Case Reports/Case Series	Actionable	In a Phase II trial, Tunlametinib (HL-085) treatment resulted in a confirmed objective response rate of 35.8% (34/95, all partial responses), a median progression-free survival of 4.2 months, disease control rate of 72.6% (69/95), median duration of response of 6.1 months, and median overall survival of 13.7 months in Chinese patients with advanced melanoma harboring NRAS mutations including NRAS Q61R (40%), Q61K (29.5%), and G12D (9.5%) (PMID: 38479118; NCT05217303).	38479118

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