Selective Oral MEK1/2 Inhibitor Pimasertib in Metastatic Melanoma: Antitumor Activity in a Phase I, Dose-Escalation Tria
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ORIGINAL RESEARCH ARTICLE
Selective Oral MEK1/2 Inhibitor Pimasertib in Metastatic Melanoma: Antitumor Activity in a Phase I, Dose‑Escalation Trial Céleste Lebbé1 · Antoine Italiano2,3 · Nadine Houédé4 · Ahmad Awada5 · Philippe Aftimos5 · Thierry Lesimple6 · Monica Dinulescu7 · Jan H. M. Schellens8,9 · Suzanne Leijen8 · Sylvie Rottey10 · Vibeke Kruse10 · Richard Kefford11 · Eric Raymond12 · Sandrine Faivre13 · Celine Pages1 · Carlos Gomez‑Roca14 · Armin Schueler15 · Samantha Goodstal16 · Giorgio Massimini17 · Jean‑Pierre Delord14
© Springer Nature Switzerland AG 2020
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
Key Points Pimasertib, an MEK 1/2 inhibitor, has clinical activity in advanced melanoma. Electronic supplementary material The online version of this article (https://doi.org/10.1007/s11523-020-00767-1) contains supplementary material, which is available to authorized users.
Eleven of 89 patients responded (12.4%), 6 of whom responded for > 24 weeks. Treatment response was most common in
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