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

Autor: Lebbé C; Dermatology and CIC, AP-HP, Saint Louis Hospital, and Université de Paris, INSERM U976, Paris, France. celeste.lebbe@aphp.fr., Italiano A; Early Phase Trials and Sarcoma Units, Institut Bergonié, Bordeaux, France.; University of Bordeaux, Bordeaux, France., Houédé N; Medical Oncology, Institut de Cancérologie du Gard, CHU Caremeau, Nîmes, France., Awada A; Oncology Médicine Department, Institut Jules Bordet, Université Libre de Bruxelles, Brussels, Belgium., Aftimos P; Oncology Médicine Department, Institut Jules Bordet, Université Libre de Bruxelles, Brussels, Belgium., Lesimple T; Medical Oncology Department, Comprehensive Cancer Center Eugène Marquis, Rennes, France., Dinulescu M; Department of Dermatology, Rennes University Hospital, Rennes, France., Schellens JHM; Division of Medical Oncology, Department of Clinical Pharmacology, The Netherlands Cancer Institute, Amsterdam, The Netherlands.; Utrecht Institute for Pharmaceutical Sciences (UIPS), Utrecht, The Netherlands., Leijen S; Division of Medical Oncology, Department of Clinical Pharmacology, The Netherlands Cancer Institute, Amsterdam, The Netherlands., Rottey S; Department of Medical Oncology, Ghent University Hospital and Heymans Institute of Pharmacology, Ghent University, Ghent, Belgium., Kruse V; Department of Medical Oncology, Ghent University Hospital and Heymans Institute of Pharmacology, Ghent University, Ghent, Belgium., Kefford R; Crown Princess Mary Cancer Centre Westmead Hospital, Faculty of Medicine and Health Sciences, Macquarie University, and Melanoma Institute Australia, Sydney, NSW, Australia., Raymond E; Medical Oncology, Groupe Hospitalier Paris St Joseph, Paris, France., Faivre S; Medical Oncology, Beaujon University Hospital, Clichy, France., Pages C; Dermatology and CIC, AP-HP, Saint Louis Hospital, and Université de Paris, INSERM U976, Paris, France., Gomez-Roca C; Clinical Research Unit, Institut Universitaire du Cancer, Oncopole, Toulouse, France., Schueler A; Global Biostatistics and Epidemiology, EMD Serono Research and Development Institute, Inc. (an affiliate of Merck KGaA, Darmstadt, Germany), Billerica, MA, USA., Goodstal S; Translational Research, EMD Serono Research and Development Institute, Inc. (an affiliate of Merck KGaA, Darmstadt, Germany), Billerica, MA, USA., Massimini G; Early Clinical Oncology Global Clinical Development Biopharma, Merck KGaA, Darmstadt, Germany., Delord JP; Clinical Research Unit, Institut Universitaire du Cancer, Oncopole, Toulouse, France.
Jazyk: angličtina
Zdroj: Targeted oncology [Target Oncol] 2021 Jan; Vol. 16 (1), pp. 47-57.
DOI: 10.1007/s11523-020-00767-1
Abstrakt: 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.
Databáze: MEDLINE
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