Phase I pharmacokinetic study of an oral, small-molecule MEK inhibitor tunlametinib in patients with advanced NRAS mutant melanoma

Abstract

Background: Malignant melanoma is an aggressive disease. Tunlametinib (HL-085) is a potent, selective, and orally bioavailable MEK1/2 inhibitor. The objective of this study was to determine the pharmacokinetics (PK) of tunlametinib and its main metabolite M8 in patients with NRAS-mutant melanoma following a single dose and multiple doses in a phase I safety and PK study.Methods: A multiple-center phase I study was performed in patients with melanoma including dose-escalation phase and dose-expansion phase. PK following a single oral dose and multiple doses of 0.5–18 mg twice daily was assessed.Results: A total of 30 participants were included in the dose escalation phase and then 11 patients were included in the dose-expansion phase (12 mg twice daily). Tunlametinib plasma concentration rapidly increased after dosing, with a Tmax of 0.5–1 h. Mean elimination half-life (t1/2) was dose-independent and had a range from 21.84 to 34.41 h. Mean apparent clearance (CL/F) and distribution volume (V/F) were 28.44–51.93 L/h and 1199.36–2009.26 L, respectively. The average accumulation ratios of AUC and Cmax after the multiple administration of tunlametinib were 1.64–2.73 and 0.82–2.49, respectively. Tunlametinib was rapidly transformed into the main metabolite M8 and M8 reached the peak concentration about 1 h after administration. Mean t1/2 of M8 was 6.1–33.54 h. The body exposure of M8 in plasma was 36%–67% of that of tunlametinib. There were general dose-proportional increases in maximum concentration (Cmax) and area under the curve (AUC) of tunlametinib and M8 both in the single dose phase and in the multiple doses phase.Conclusion: Tunlametinib was absorbed rapidly and eliminated at a medium speed after drug withdrawal. Pharmacokinetic body exposure increased in general dose-proportional manner from 0.5 mg up to 18 mg. Slight accumulation was found after multiple oral doses. The pharmacokinetics of tunlametinib and its metabolite suggest that twice daily dosing is appropriate for tunlametinib.

Preclinical characterization of tunlametinib, a novel, potent, and selective MEK inhibitor

“…Overall, our findings constitute a preclinical data of tunlametinib and offer a precision medicine option available that could be tailored to individual mutations and cancers. These data supported the progression of tunlametinib into a first-in-human clinical study ( Zhao et al, 2022 ; Wang et al, 2023 ). Currently, the first-in-human phase 1 ( ClinicalTrials.gov number, NCT03973151, NCT04683354) and pivotal clinical study of tunlametinib (NCT05217303) as monotherapy, and the phase 1 study as combination therapy (NCT05263453) have been completed.…”

“…Tunlametinib emerged as the top candidate from an optimization of molecular structure, as this compound incorporated both improved potency and favorable PK properties. Trametinib, as the first approved MEK inhibitor, has blood drug accumulation with the mean accumulation ratio (day15/day1) with repeat dose of 2 mg approximate 6.0 ( Food and Drug Administration, 2013 ), whereas tunlametinib showed minimal drug accumulation in preclinical and clinical studies ( Zhao et al, 2022 ). Compared with other three FDA-approved MEK inhibitors, tunlametinib showed much more potent both in vitro and in vivo .…”

“…Tunlametinib exhibited both enhanced efficacy and favorable PK profile in preclinical study, thereby overcoming the shortcomings of the current MEK inhibitors. In the phase 1 study of tunlametinib monotherapy for NRAS-mutant melanoma, tunlametinib demonstrated acceptable tolerability and substantial clinical activity as well as favorable PK profiles ( Zhao et al, 2022 ; Wang et al, 2023 ). The encouraging efficacy and well tolerability were further verified in a phase 2 trial ( Si et al, 2023 ).…”

First-in-human phase I dose-escalation and dose-expansion trial of the selective MEK inhibitor HL-085 in patients with advanced melanoma harboring NRAS mutations

“…HL-085 exposure (area under the curve and maximum plasma concentration) is close to dose proportional over the dose range of 0.5-15 mg twice daily with minimal accumulation. The mean plasma terminal half-life is 21.84 h-34.41 h. More detailed results of the pharmacokinetic analysis of the parent study are described in another article which was recently published by Qian Zhao et al [23].…”

Tunlametinib (HL-085) plus vemurafenib in patients with advanced BRAF V600-mutant solid tumors: an open-label, single-arm, multicenter, phase I study

“…Tunlametinib (HL-085) is a novel, selective inhibitor of MEK that exhibits high inhibitory activity against MEK1 and moderate activity against MEK2, developed by Shanghai Kechow Pharma, Inc., Shanghai, the People’s Republic of China [ 15 ]. In preclinical studies, tunlametinib showed antitumor activity in a variety of tumor cell lines and tumor xenograft models.…”