Selective Oral MEK1/2 Inhibitor Pimasertib in Metastatic Melanoma: Antitumor Activity in a Phase I, Dose-Escalation Trial.
- Type de publi. : Article dans une revue
- Date de publi. : 01/01/1970
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Auteurs :
Céleste LebbéAntoine ItalianoNadine HouédéAhmad AwadaPhilippe AftimosThierry LesimpleMonica DinulescuJan SchellensSuzanne LeijenSylvie RotteyVibeke KruseRichard KeffordEric RaymondSandrine FaivreCeline PagesCarlos Alberto Gomez-RocaArmin SchuelerSamantha GoodstalGiorgio MassiminiJean-Pierre Delord
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Organismes :
Service de Dermatologie [AP-HP Hôpital Saint-Louis]
Immunologie humaine, physiopathologie & immunothérapie
Institut Bergonié [Bordeaux]
Université de Bordeaux
Institut de Cancérologie du GARD ICG - CHU Nîmes
Institut Jules Bordet [Bruxelles]
Institut Jules Bordet [Bruxelles]
CRLCC Eugène Marquis
Service de Dermatologie [Rennes] = Dermatology [Rennes]
Netherlands Cancer Institute
Utrecht Institute for Pharmaceutical Sciences
Netherlands Cancer Institute
Ghent University Hospital
Heymans Institute of Pharmacology
Ghent University Hospital
Heymans Institute of Pharmacology
Westmead Hospital [Sydney]
Macquarie University [Sydney]
Melanoma Institute Australia [Sydney, NSW, Australia]
Département de Rythmologie-Stimulation- Hôpital Saint-Joseph, Paris
Hôpital Beaujon [AP-HP]
Service de Dermatologie [AP-HP Hôpital Saint-Louis]
Immunologie humaine, physiopathologie & immunothérapie
Institut Universitaire du Cancer de Toulouse - Oncopole
Merck KGaA [Darmstadt, Germany]
Merck KGaA [Darmstadt, Germany]
Merck KGaA [Darmstadt, Germany]
Institut Universitaire du Cancer de Toulouse - Oncopole
- Publié dans Targeted Oncology le 01/11/2020
Résumé : 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.
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