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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.
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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 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
Molecular Profile Indication/Tumor Type Response Type Therapy Name Approval Status Evidence Type Efficacy Evidence References
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 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 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 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 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
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