TY - JOUR
T1 - Selective oral MEK1/2 inhibitor pimasertib in metastatic melanoma
T2 - antitumor activity in a phase I, dose-escalation trial
AU - Lebbé, Céleste
AU - Italiano, Antoine
AU - Houédé, Nadine
AU - Awada, Ahmad
AU - Aftimos, Philippe
AU - Lesimple, Thierry
AU - Dinulescu, Monica
AU - Schellens, Jan H. M.
AU - Leijen, Suzanne
AU - Rottey, Sylvie
AU - Kruse, Vibeke
AU - Kefford, Richard
AU - Raymond, Eric
AU - Faivre, Sandrine
AU - Pages, Celine
AU - Gomez-Roca, Carlos
AU - Schueler, Armin
AU - Goodstal, Samantha
AU - Massimini, Giorgio
AU - Delord, Jean Pierre
PY - 2021/1
Y1 - 2021/1
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=85095785122&partnerID=8YFLogxK
U2 - 10.1007/s11523-020-00767-1
DO - 10.1007/s11523-020-00767-1
M3 - Article
C2 - 33211315
AN - SCOPUS:85095785122
SN - 1776-2596
VL - 16
SP - 47
EP - 57
JO - Targeted Oncology
JF - Targeted Oncology
IS - 1
ER -