Selective oral MEK1/2 inhibitor pimasertib in metastatic melanoma: antitumor activity in a phase I, dose-escalation trial

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

*Corresponding author for this work

    Research output: Contribution to journalArticlepeer-review

    5 Citations (Scopus)


    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:, NCT00982865.

    Original languageEnglish
    Pages (from-to)47-57
    Number of pages11
    JournalTargeted Oncology
    Issue number1
    Publication statusPublished - Jan 2021


    Dive into the research topics of 'Selective oral MEK1/2 inhibitor pimasertib in metastatic melanoma: antitumor activity in a phase I, dose-escalation trial'. Together they form a unique fingerprint.

    Cite this