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

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.

• Authors: Céleste Lebbé, Antoine Italiano, Nadine Houédé, Ahmad Awada, Philippe Aftimos, Thierry Lesimple, Monica Dinulescu, Jan H M Schellens, Suzanne Leijen, Sylvie Rottey, Vibeke Kruse, Richard Kefford, Eric Raymond, Sandrine Faivre, Celine Pages, Carlos Gomez-Roca, Armin Schueler, Samantha Goodstal, Giorgio Massimini, Jean-Pierre Delord
• Journal: Targeted oncology (Target Oncol) Vol. 16 Issue 1 Pg. 47-57 (01 2021) ISSN: 1776-260X [Electronic] France
• PMID: 33211315 (Publication Type: Clinical Trial, Phase I, Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

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

Topics

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