Vemurafenib in Chinese patients with BRAFV600 mutation\u2013positive unresectable or metastatic melanoma: an open-label, multicenter phase I study

Lu Si,Zhen Xu,Nicole Richie,Xiaoshi Zhang,Weijiang Zhang,Lili Mao,Qiudi Jiang,Jun Guo,Xuan Wang,Lilian Bu

doi:10.1186/s12885-018-4336-3

Abstract

BackgroundMelanoma is a rare, deadly disease without effective treatment options in China. Vemurafenib is a selective inhibitor of oncogenic BRAFV600 kinase approved in more than 90 countries, based on results obtained primarily in Caucasian patients. Limited data are available regarding the efficacy and safety of vemurafenib in Asian patients.MethodsThis phase I study investigated the pharmacokinetics, efficacy, and tolerability of vemurafenib (960 mg twice daily) in Chinese patients with BRAFV600 mutation–positive unresectable or metastatic melanoma. The study included two cohorts: a pharmacokinetic cohort (n = 20) and an expansion cohort (n = 26).ResultsAfter 21 days of dosing, vemurafenib demonstrated marked accumulation and relatively constant steady-state exposure over the dosing period. Confirmed best overall response rate was 52.2% (95% CI 37.0–67.1%). Median progression-free survival was 8.3 months (95% CI 5.7–10.9%); median overall survival was 13.5 months (95% CI 12.2%–not estimable). The most common adverse events were dermatitis acneiform, arthralgia, diarrhea, blood cholesterol level increase, blood bilirubin level increase, melanocytic nevus, and alopecia. A total of nine grade 3 or 4 adverse events were reported in seven patients (15.2%).ConclusionOverall, vemurafenib showed a favorable benefit-risk profile among Chinese patients. Pharmacokinetics, safety, and efficacy were generally consistent with those reported in Caucasian patients.Trial registrationClinicalTrials.gov identification: NCT01910181. Registered 29 July 2013, prospectively registered.

Highlights

Melanoma is a rare, deadly disease without effective treatment options in China
Twenty patients were enrolled in the pharmacokinetic cohort and 26 were enrolled in the expansion cohort
One patient was excluded from analysis of t1⁄2 and volume of distribution because Terminal elimination rate constant (Kel) could not be reliably estimated owing to insufficient concentration timepoint data during the elimination phase

Summary

Introduction

Deadly disease without effective treatment options in China. Several new treatment options for metastatic melanoma have emerged in the past 5 years, including monoclonal antibodies targeting the programmed cell death 1 receptor and cytotoxic T-lymphocyte–associated antigen 4 and small-molecule inhibitors of BRAF and MEK. Clinical trials for these agents have been conducted almost exclusively in Caucasian populations. These agents are largely considered investigational in China [3]. Despite safety concerns and poor overall survival (OS), dacarbazine has remained standard first-line therapy for metastatic melanoma in China [3, 4]

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