选择性口服 MEK1/2 抑制剂 Pimasertib 治疗转移性黑色素瘤：I 期剂量递增试验的抗肿瘤活性。

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

机构信息

Dermatology and CIC, AP-HP, Saint Louis Hospital, and Université de Paris, INSERM U976, Paris, France.

Early Phase Trials and Sarcoma Units, Institut Bergonié, Bordeaux, France.

出版信息

Target Oncol. 2021 Jan;16(1):47-57. doi: 10.1007/s11523-020-00767-1.

DOI:10.1007/s11523-020-00767-1

PMID:33211315

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.

摘要

背景

派马替尼是一种选择性的、强效的丝裂原活化蛋白激酶激酶（MEK）1/2 抑制剂。

目的

本研究旨在描述派马替尼在来自派马替尼首次人体研究的局部晚期/转移性黑色素瘤患者中，在具有药理活性剂量下的疗效、安全性和药效学。

方法

这是一项 I 期、开放标签、两部分、剂量递增研究。第 1 部分在实体瘤患者中进行，以确定最大耐受剂量，而第 2 部分仅限于晚期/转移性黑色素瘤患者。终点包括安全性、药效学和抗肿瘤活性。我们仅从研究的两部分报告黑色素瘤患者的数据。

结果

共有 93 名黑色素瘤患者接受了派马替尼治疗，其中 89 名患者在研究的两部分的四个剂量方案中接受了具有药理活性的剂量（28-255mg/天）。客观缓解率为 12.4%（11/89）：完全缓解（n=1）和部分缓解（PR；n=10）。6 名患者的缓解时间超过 24 周。11 名缓解者中有 9 名肿瘤具有 B-Raf 原癌基因丝氨酸/苏氨酸激酶（BRAF；n=6）和/或 NRAS 原癌基因 GTP 酶（NRAS；n=3）突变。46 名患者疾病稳定（SD）。在眼部黑色素瘤患者（n=13）中，最佳总体缓解为 PR（n=1）、SD（n=11）和疾病进展（n=1）。治疗后 2 小时内磷酸化细胞外信号调节激酶（pERK）水平显著降低，并且持续每日两次给药可保持抑制作用。在 8 名患者中报告了与治疗相关的、复发的、3 级或更高级别的不良事件，包括腹泻以及皮肤和眼部事件。