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|Ref Type||Journal Article|
|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.|
|Date||2023 Jan 04|
|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.|
|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 G12S||melanoma||predicted - sensitive||HL-085||Case Reports/Case Series||Actionable||In a Phase I trial, 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||HL-085||Case Reports/Case Series||Actionable||In a Phase I trial, 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|
|NRAS act mut||melanoma||predicted - sensitive||HL-085||Phase I||Actionable||In a Phase I trial, 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|