Selective Oral MEK1/2 Inhibitor Pimasertib in Metastatic Melanoma: Antitumor Activity in a Phase I, Dose-Escalation Trial

Target Oncol. 2021 Jan;16(1):47-57. doi: 10.1007/s11523-020-00767-1.

Abstract

Background: Pimasertib is a selective, potent mitogen-activated protein kinase kinase (MEK) 1/2 inhibitor.

Objectives: The aim of this study was to describe the efficacy, safety, and pharmacodynamics of pimasertib at pharmacologically active doses in a cohort of patients with locally advanced/metastatic melanoma from a first-in-human study of pimasertib.

Methods: This was a phase I, open-label, two-part, dose-escalation study. Part 1 was conducted in patients with solid tumors and identified the maximum tolerated dose, while Part 2 was restricted to patients with advanced/metastatic melanoma. Endpoints included safety, pharmacodynamics, and antitumor activity. We present data for patients with melanoma only from both parts of the study.

Results: In total, 93 patients with melanoma received pimasertib, 89 of whom received pharmacologically active doses (28-255 mg/day) across four dose regimens in the two parts of the study. The objective response rate was 12.4% (11/89): complete response (n = 1) and partial response (PR; n = 10). Six patients responded for > 24 weeks. Nine of the 11 responders had tumors with B-Raf Proto-Oncogene, Serine/Threonine Kinase (BRAF; n = 6) and/or NRAS Proto-Oncogene, GTPase (NRAS; n = 3) mutations. Forty-six patients had stable disease (SD). In patients with ocular melanoma (n = 13), best overall response was PR (n = 1), SD (n = 11), and disease progression (n = 1). Phosphorylated extracellular signal-regulated kinase (pERK) levels were substantially reduced within 2 h of treatment and inhibition was sustained with continuous twice-daily dosing. Treatment-related, recurrent, grade 3 or higher adverse events were reported in eight patients, including diarrhea, and skin and ocular events.

Conclusion: Results from this phase I study indicate that pimasertib has clinical activity in patients with locally advanced/metastatic melanoma, particularly BRAF- and NRAS-mutated tumors, at clinically relevant doses associated with pERK inhibition in peripheral blood mononuclear cells.

Trial registration: ClinicalTrials.gov, NCT00982865.

Publication types

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

MeSH terms

  • Adult
  • Aged
  • Aged, 80 and over
  • Female
  • Humans
  • Male
  • Melanoma / drug therapy*
  • Middle Aged
  • Niacinamide / analogs & derivatives*
  • Niacinamide / pharmacology
  • Niacinamide / therapeutic use
  • Protein Kinase Inhibitors / pharmacology
  • Protein Kinase Inhibitors / therapeutic use*
  • Proto-Oncogene Mas

Substances

  • MAS1 protein, human
  • N-(2,3-dihydroxypropyl)-1-((2-fluoro-4-iodophenyl)amino)isonicotinamide
  • Protein Kinase Inhibitors
  • Proto-Oncogene Mas
  • Niacinamide

Associated data

  • ClinicalTrials.gov/NCT00982865