Background
Melanoma is relatively rare in China, with a reported incidence of 0.6 per 100,000 persons in 2012 [
1]. However, most Chinese patients with melanoma (> 90%) are diagnosed with locally advanced disease (stage II or higher) and prognosis is poor, particularly for those with stage IV disease, among whom the estimated 5-year survival rate is 4.6% [
2].
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. However, clinical trials for these agents have been conducted almost exclusively in Caucasian populations. Consequently, 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].
Approximately 50% of melanomas in Caucasian patients harbor
BRAF mutations, resulting in constitutive
BRAF kinase activity [
5‐
7]. Among Chinese patients with melanoma, the rate of
BRAF mutation is approximately 25% [
8]. Vemurafenib is a highly selective inhibitor of oncogenic
BRAF kinase. In the pivotal phase III study (BRIM-3), vemurafenib significantly improved progression-free survival (PFS) and OS compared with dacarbazine in patients with
BRAFV600-mutated metastatic melanoma [
9,
10]. More than 99% of patients enrolled in BRIM-3 were Caucasian [
9], and limited data are available regarding the efficacy and safety of vemurafenib in Asian patients. This phase I study evaluated the pharmacokinetics, efficacy, and safety of vemurafenib in Chinese patients with
BRAFV600 mutation–positive unresectable or metastatic melanoma.
Methods
Study design
This open-label, multicenter, phase I study enrolled two cohorts: a pharmacokinetic cohort and an expansion cohort. For the pharmacokinetic cohort, patients received treatment in three periods after a 28-day screening period. In period A (days 1–21), patients received oral vemurafenib 960 mg twice daily. Patients fasted overnight for at least 8 h before and at least 4 h after the morning dose on days 1 and 21. Light snacks (crackers, toast, water, and juice) were allowed in the 4-h post-dose period. All other doses were administered either 1 h before or 2 h after a meal. Only the morning dose was administered on day 21. In period B (days 22–27), patients temporarily discontinued vemurafenib to enable characterization of the elimination profile. In period C (day 28 onwards), patients continued to receive vemurafenib 960 mg twice daily until disease progression, unacceptable toxicity, withdrawal of consent, or discontinuation for any other reason.
Enrollment in the expansion cohort was initiated after completion of recruitment into the pharmacokinetic cohort. In the expansion cohort, all patients received vemurafenib 960 mg twice daily until progressive disease, unacceptable toxicity, withdrawal of consent, or discontinuation for any other reason. Dose modifications (temporary interruption or dose reductions) were allowed within both cohorts for management of symptomatic adverse events (AEs).
This study was conducted in accordance with International Congress on Harmonisation guidelines for Good Clinical Practice, the principles of the Declaration of Helsinki, and local regulations. All patients provided written informed consent. This trial was registered prospectively at
ClinicalTrials.gov (ID, NCT01910181) on July 29, 2013. The trial was designed jointly by the corresponding author and the sponsor (F. Hoffmann-La Roche Ltd). Data were collected by the site investigators and were retained and analyzed by the sponsor. All authors had full access to the data.
Patients
Chinese patients ≥18 years of age with histologically confirmed metastatic melanoma (unresectable stage IIIC or stage IV) positive for BRAFV600 mutation by cobas® BRAF V600 Mutation Test (Roche Molecular Diagnostics, Pleasanton, CA, USA) were eligible. Other key inclusion criteria included measurable disease according to Response Evaluation Criteria in Solid Tumors, version 1.1 (RECIST v1.1); Eastern Cooperative Oncology Group performance status 0–1; adequate hematologic, renal, and liver function; life expectancy > 3 months; and absence of active central nervous system metastases. Patients could be treatment-naive or have previously received systemic therapy (excluding BRAF or MEK inhibitors).
Outcomes and assessments
The primary objective was to evaluate the pharmacokinetics of vemurafenib 960 mg twice daily in Chinese patients, including maximal concentration (C
max); time to maximal concentration (t
max); area under the concentration-time curve from 0 to 8 hours (AUC
0-8h)
, AUC
0-12h, and AUC
0-168h; trough concentration (C
trough); accumulation ratio (defined as AUC
0-8h on day 21/AUC
0-8h on day 1); terminal elimination rate constant (K
el); and terminal half-life (t
½). The schedule of assessments is in the Additional file
1. Pharmacokinetic parameters were calculated using noncompartmental analysis (Phoenix WinNonlin, version 6.2; Pharsight, a Certara company, Princeton, NJ, USA).
Efficacy endpoints included best overall response rate (BORR) according to RECIST v1.1, confirmed by repeat assessment at least 4 weeks after criteria were first met, PFS, OS, and duration of response (DOR). Tumor assessments (computed tomography or magnetic resonance imaging) were obtained at screening, day 1 of cycle 3, and every 2 cycles thereafter (or as clinically indicated) until documented disease progression. DOR, PFS, and OS were estimated using the Kaplan-Meier method.
Safety assessments consisted of monitoring and recording of AEs, serious AEs, and nonserious AEs of special interest; protocol-specified laboratory assessments; vital signs; and other protocol-specified tests. AEs were graded according to National Cancer Institute Common Terminology Criteria for Adverse Events, version 4.0. Patients were followed for safety for 28 days after the last dose of study medication or until resolution of drug-related AEs. All patients who received at least one dose of vemurafenib were to be followed for evaluation of cutaneous squamous cell carcinoma (cuSCC) until 6 months after discontinuation of study treatment, or until death, withdrawal of consent, or loss to follow-up, whichever occurred first.
The pharmacokinetic analysis population included all patients who provided sufficient pharmacokinetic data to obtain at least one of the primary pharmacokinetic variables. The safety population included all patients who received at least one dose of vemurafenib, and the tumour response population included all patients.
Statistical analysis
No formal sample size calculation was performed. The sample size of 20 patients in the pharmacokinetic cohort was chosen to characterize the vemurafenib pharmacokinetic profile with consideration of interpatient variability. With 20 patients enrolled in the pharmacokinetic cohort, at least 10 patients would be expected to complete the pharmacokinetic portion of the study. A total of 45 patients (20 in the pharmacokinetic cohort and 25 in the expansion cohort) would give a Clopper-Pearson 95% CI of 26–56% for BORR, assuming the target BORR (confirmed) is 40%.
Discussion
To date, this is the largest study to evaluate the efficacy and safety of vemurafenib in an Asian population. Vemurafenib demonstrated marked accumulation and relatively constant steady-state exposure in Chinese patients, consistent with previous observations in predominantly Caucasian populations [
11,
12]. Comparison of pharmacokinetic results in Chinese patients with melanoma in the current study with those in predominantly Caucasian patients in a previous study with a similar design show that vemurafenib exposures were higher in Chinese patients (Additional file
4: Table S1) [
11]. On day 1, mean AUC
0-8h and C
max in Chinese patients were 39% and 44% higher, respectively, than those in predominantly Caucasian populations. More importantly, at steady state (day 15 in the previous Caucasian pharmacokinetic study and day 21 in the current study), mean AUC
0-8h and C
max (day 21) were 28% and 26% higher, respectively, than in predominantly Caucasian populations (day 15) [
11].
These differences in exposure may be partially explained by increases in vemurafenib trough concentrations (C
trough) from days 15 to 21, although it is unclear whether these increases in concentration were caused by continuous accumulation or intrapatient variability. While a lower average body weight is frequently identified as a possible reason for increased drug exposure in Asians relative to Caucasians, body weight or body mass index has not been identified as a covariant for vemurafenib pharmacokinetic parameters from population pharmacokinetic analysis of data from phase I, II, and III studies [
13]. Furthermore, although exposure was higher in Chinese patients, it was within the range observed in predominantly Caucasian populations. Additionally, the differences in mean exposure are unlikely to lead to clinically meaningful differences in toxicity, given the previous demonstration of lack of a significant effect of vemurafenib exposure within the current range on liver laboratory values or skin toxicities [
13]. Although exposure-dependent QT interval prolongation was observed in a substudy of the phase II BRIM-2 study [
13], no patient in this study had a post-baseline corrected QT interval (Fridericia’s formula) > 500 msec.
The efficacy of vemurafenib in Chinese patients with
BRAFV600-mutated unresectable or metastatic melanoma was similar to that observed in predominantly Caucasian populations (Additional file
5: Table S2) [
10,
12]. In the current study, patients could have been treatment-naive or have previously received systemic therapy. Therefore, efficacy results were compared with patients treated with vemurafenib in the phase II BRIM-2 study (previously treated with at least one prior line of systemic therapy) [
12] and the pivotal BRIM-3 study (treatment-naive) [
10]. After similar median follow-up durations, the confirmed BORR in Chinese patients (52%) was similar to that reported in predominantly Caucasian populations with previously treated and treatment-naive disease (both 57%) [
10,
12]. Although the CR rate in the current study in Chinese patients was numerically lower than that reported in the vemurafenib arm of BRIM-3 (2% vs. 6%, respectively), it remains comparable, as indicated by the overlapping 95% CI (0.06–11.53 in this study vs. 3.4–8.7 in BRIM-3) [
10]. Furthermore, the percentage of LDH elevated and M1C was also comparable between the current study and BRIM-3 (LDH elevated: 41% vs. 42%; M1C: 61% vs. 66%, respectively). PFS (8.3 vs. 6.8 and 6.9 months, respectively) and OS (13.5 vs. 15.9 and 13.6 months, respectively) were also similar between Chinese and predominantly Caucasian populations [
10,
12]. A post hoc subgroup analysis of the current study showed no substantial differences in efficacy (BORR, PFS, OS) among patients who were treatment-naive and those who had received one, two, or more than two previous lines of systemic therapy, although comparisons were limited by small patient numbers in each subgroup.
Vemurafenib was generally well tolerated in Chinese patients. Compared with predominantly Caucasian patients treated with vemurafenib in the pivotal BRIM-3 study [
9,
10], Chinese patients had higher incidences of blood cholesterol level increase (59% vs. < 1%), hypertriglyceridemia (22% vs. < 1%), total bile acid increase (22% vs. 0%), hyperuricemia (17% vs. < 1%), blood bilirubin level increase (54% vs. 9%), leukopenia (22% vs. 0%), proteinuria (24% vs. < 1%), and melanocytic nevus (52% vs. 10%) (Additional file
6: Table S3) [
10]. Lipid panels were not done as part of the BRIM-3 protocol, in contrast to formal data collection of the full fasting lipid profile required in the current study; as a result, no conclusions can be drawn from these comparisons. In the current study, the majority of these laboratory AEs met the criteria as AEs because the events were considered medically significant by investigators but were not accompanied by clinical symptoms, did not require a change in study treatment, and did not result in medical intervention. Moreover, apart from one event of grade 3 blood cholesterol level increase leading to treatment interruption, all of these events were grade 1–2, asymptomatic, and did not necessitate dose modification. Therefore, it is highly unlikely that these observed differences in clinical AEs impact the overall benefit/risk evaluation of vemurafenib.
In the BRIM-3 study, grade 3 cuSCC and grade 3 keratoacanthoma occurred in 19% (65 of 337) and 10% of patients (34 of 337) in the vemurafenib arm, respectively [
9,
10]. In contrast, no such events were observed in Chinese patients in the current study. Similarly, no cuSCC or keratoacanthoma was observed in a phase I/II study of vemurafenib in Japanese patients with melanoma [
14], and only one case of cuSCC was reported in an early post-marketing phase vigilance study that followed 95 vemurafenib-treated Japanese patients with metastatic melanoma [
15]. This could potentially be related to differences between Asian and Caucasian populations. Because plasma concentrations of vemurafenib were generally consistent between Asian and Caucasian patients, this difference could be attributed to differences in culture and lifestyle, such as duration of exposure to sunlight, as well as differences in genetic susceptibility. Considering the relatively small sample sizes of the current study and the Japanese study (
N = 11), actual incidences of these skin disorders in Asian patients must be confirmed in larger patient populations.