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

BMC Med. 2023 Jan 4;21(1):2. doi: 10.1186/s12916-022-02669-7.


Background: 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.

Methods: 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.

Results: 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.

Conclusions: The HL-085 showed acceptable tolerability and substantial clinical activity in patients with advanced melanoma harboring NRAS mutations.

Trial registration: Trial registration number: NCT03973151.

Keywords: Advanced melanoma; HL-085; MEK inhibitor; NRAS mutation, Circulating tumor DNA.

Publication types

  • Clinical Trial, Phase I
  • Multicenter Study
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Antineoplastic Agents / adverse effects
  • Antineoplastic Agents / therapeutic use
  • GTP Phosphohydrolases / genetics
  • GTP Phosphohydrolases / therapeutic use
  • Humans
  • Melanoma* / drug therapy
  • Melanoma* / genetics
  • Membrane Proteins / genetics
  • Mitogen-Activated Protein Kinase Kinases* / antagonists & inhibitors
  • Mutation
  • Progression-Free Survival
  • Protein Kinase Inhibitors / adverse effects
  • Protein Kinase Inhibitors / therapeutic use


  • Antineoplastic Agents
  • GTP Phosphohydrolases
  • Membrane Proteins
  • Mitogen-Activated Protein Kinase Kinases
  • NRAS protein, human
  • Protein Kinase Inhibitors

Associated data