Pimasertib has clinical activity in patients with locally advanced/metastatic melanoma
November 26, 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
Source:
Lebbé, C., Italiano, A., Houédé, N. et al. Selective Oral MEK1/2 Inhibitor Pimasertib in Metastatic Melanoma: Antitumor Activity in a Phase I, Dose-Escalation Trial. Targ Oncol (2020). https://doi.org/10.1007/s11523...