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Ref Type

Journal Article

PMID

(36600247)

Authors

Wang X, Luo Z, Chen J, Chen Y, Ji D, Fan L, Chen L, Zhao Q, Hu P, Sun P, Jia Z, Guo J, Si L

Title

First-in-human phase I dose-escalation and dose-expansion trial of the selective MEK inhibitor HL-085 in patients with advanced melanoma harboring NRAS mutations.

Journal	Vol	Issue	Date	Pages	Journal Short Title
BMC medicine	21	1	2023 Jan 04	2	BMC Med

URL

Abstract Text

HL-085 is a selective, orally administered MEK1/2 inhibitor. We aimed to evaluate the safety and efficacy of HL-085 in patients with advanced melanoma harboring NRAS mutations.This was a multicenter phase 1 study. HL-085 was administered twice daily in a standard 3 + 3 dose-escalation design (10 dose cohorts; 0.5-18 mg twice daily), followed by dose expansion at the recommended phase II dose (RP2D). The primary endpoints included tolerability, dose-limiting toxicity (DLT), maximum tolerated dose (MTD) and RP2D.Between September 13, 2017, and January 18, 2021, 42 patients were enrolled (dose escalation phase: n = 30; dose expansion phase: n = 12). No DLT was reported during dose escalation and MTD was not reached with HL-085 doses up to 18 mg twice daily. The RP2D was 12 mg twice daily. The most common all-grade drug-related adverse events (AEs) across all dose levels were rash (61.9%), increased creatine phosphokinase (CK, 59.5%), face edema (50.0%), increased aspartate aminotransferase (47.6%), peripheral edema (40.5%), diarrhea (33.3%), alanine aminotransferase (33.3%), and paronychia (19.0%), most of which were grade 1 and 2. Most frequency of grade ≥ 3 AEs were CK (14.2%), asthenia (7.1%), peripheral edema (4.8%), and acneiform dermatitis (4.8%). In the cohort of 12 mg twice daily dose (15 patients), confirmed objective response rate was 26.7%; disease control rate was 86.7%; median duration of response was 2.9 months; median progression-free survival was 3.6 months.The HL-085 showed acceptable tolerability and substantial clinical activity in patients with advanced melanoma harboring NRAS mutations.Trial registration ClinicalTrials.gov number: NCT03973151.

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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 I	Actionable	In a Phase I trial, Tunlametinib (HL-085) treatment demonstrated acceptable tolerability and resulted in an objective response rate (ORR) of 14.3% (6/42; all partial responses), a disease control rate (DCR) of 78.6%, and a median progression-free survival (PFS) of 3.0 months in patients with advanced melanoma harboring NRAS mutations, and an ORR of 26.7% (4/15), a DCR of 86.7%, and median PFS of 3.6 months at the recommended Phase II dose (PMID: 36600247; NCT03973151).	36600247
NRAS G12S	melanoma	predicted - sensitive	Tunlametinib	Case Reports/Case Series	Actionable	In a Phase I trial, Tunlametinib (HL-085) treatment demonstrated safety and preliminary efficacy in patients with advanced melanoma harboring NRAS mutations, resulting in a partial response in a patient harboring NRAS G12S who remained on treatment for 36 weeks (PMID: 36600247; NCT03973151).	36600247
NRAS Q61R	melanoma	predicted - sensitive	Tunlametinib	Case Reports/Case Series	Actionable	In a Phase I trial, Tunlametinib (HL-085) treatment demonstrated safety and preliminary efficacy in patients with advanced melanoma harboring NRAS mutations, resulting in an objective response rate of 37.5% (3/8), a disease control rate of 75% (6/8), and a median progression-free survival of 114.0 days in patients harboring NRAS Q61R at the recommended Phase II dose (PMID: 36600247; NCT03973151).	36600247

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