Elsevier

The Lancet Oncology

Volume 15, Issue 4, April 2014, Pages 436-444
The Lancet Oncology

Articles
Vemurafenib in patients with BRAFV600 mutated metastatic melanoma: an open-label, multicentre, safety study

https://doi.org/10.1016/S1470-2045(14)70051-8Get rights and content

Summary

Background

The orally available BRAF kinase inhibitor vemurafenib, compared with dacarbazine, shows improved response rates, progression-free survival (PFS), and overall survival in patients with metastatic melanoma that has a BRAFV600 mutation. We assessed vemurafenib in patients with advanced metastatic melanoma with BRAFV600 mutations who had few treatment options.

Methods

In an open-label, multicentre study, patients with untreated or previously treated melanoma and a BRAFV600 mutation received oral vemurafenib 960 mg twice a day. The primary endpoint was safety. All analyses were done on the safety population, which included all patients who received at least one dose of vemurafenib. This report is the third interim analysis of this study. This study is registered with ClinicalTrials.gov, number NCT01307397.

Findings

Between March 1, 2011, and Jan 31, 2013, 3226 patients were enrolled in 44 countries. 3222 patients received at least one dose of vemurafenib (safety population). At data cutoff, 868 (27%) patients were on study treatment and 2354 (73%) had withdrawn, mainly because of disease progression. Common adverse events of all grades included rash (1592 [49%]), arthralgia (1259 [39%]), fatigue (1093 [34%]), photosensitivity reaction (994 [31%]), alopecia (826 [26%]), and nausea (628 [19%]). 1480 (46%) patients reported grade 3 or 4 adverse events, including cutaneous squamous cell carcinoma (389 [12%]), rash (155 [5%]), liver function abnormalities (165 [5%]), arthralgia (106 [3%]), and fatigue (93 [3%]). Grade 3 and 4 adverse events were reported more frequently in patients aged 75 years and older (n=257; 152 [59%, 95% CI 53–65] and ten [4%, 2–7], respectively) than in those younger than 75 years (n=2965; 1286 [43%, 42–45] and 82 [3%, 2–3], respectively).

Interpretation

Vemurafenib safety in this diverse population of patients with BRAFV600 mutated metastatic melanoma, who are more representative of routine clinical practice, was consistent with the safety profile shown in the pivotal trials of this drug.

Funding

F Hoffmann-La Roche.

Introduction

The global incidence of melanoma is increasing, with about 200 000 new cases and about 65 000 melanoma-associated deaths every year.1, 2 Although metastatic melanoma typically has been associated with poor prognosis, with 5-year survival of about 60% and 15% in patients with regional and distant metastases, respectively,3, 4 the therapeutic options recently changed substantially. The BRAF kinase inhibitor vemurafenib and the anti-CTLA-4 antibody ipilimumab prolonged survival in patients with metastatic melanoma and are now standard treatment options.5, 6, 7 Two additional agents, the BRAF inhibitor dabrafenib and the mitogen-activated protein kinase inhibitor trametinib have recently been approved (both in the USA, and dabrafenib in the European Union).

Clinical trial populations differ in important ways from patients in routine clinical practice. For example, patients enrolled in registration clinical trials in oncology usually have a good performance status (PS) and those with brain metastases are often excluded from enrolment.8 These points are particularly relevant in patients with advanced melanoma: about a third of patients have CNS involvement, prognosis is poor, and median survival is about 3 months.4, 9, 10 Furthermore, before the development of vemurafenib and ipilimumab, patients with advanced melanoma with an increased serum lactate dehydrogenase (LDH) concentration, another marker of poor prognosis,11 were often excluded from clinical trials. Moreover, the requirement in trials for patients with an Eastern Cooperative Oncology Group (ECOG) PS of 0 or 1, an absence of brain metastases, and a life expectancy of more than 3 months leads to an enrichment of the numbers of patients with low LDH concentrations. Last, a landmark meta-analysis of survival was done in 42 phase 2 cooperative group trials in patients with advanced melanoma between 1975 and 2005.4 The reported survival at 1 year was 4–34% (depending on sex and PS) in patients with visceral involvement in trials in which brain metastases were not excluded.

Of relevance to patients, clinicians, payers, and health technology assessment organisations such as the UK's National Institute for Health and Care Excellence is whether results from registration drug trials such as the BRIM-3 trial7 of vemurafenib versus dacarbazine can be extrapolated to real-world clinical practice. Increased access and more safety studies of patients in a setting that is better representative of clinical practice are also important in ascertaining the real frequencies of rare adverse events, such as second primary melanomas or other second primary malignancies noted in vemurafenib-treated patients.12, 13

In this study we assessed the safety of vemurafenib in patients with advanced metastatic melanoma with BRAFV600 mutations and unsatisfactory treatment options.

Section snippets

Study design and patients

This open-label, multicentre study was done in 44 countries (Europe, South America, Australia, Canada, South Korea, South Africa, and India) to assess the safety, tolerability, and efficacy of vemurafenib in untreated or previously treated patients with unresectable stage IIIC or stage IV melanoma with a BRAFV600 mutation (cobas 4800 BRAFV600 Mutation Test, Roche Molecular Systems, Branchburg, NJ, USA).14 The trial consisted of a screening period (days −28 to −1), treatment phase, follow-up

Results

From March 1, 2011, to Jan 31, 2013, 7512 patients were screened for eligibility and 3226 were enrolled in the study (figure 1). The most common reasons for study exclusion (n=4286) were negative BRAFV600 mutation status (44%) and failure to meet other eligibility criteria (7%; figure 1). 29 patients from one study centre were excluded from analyses because of significant breaches in good clinical practice protocol.

The median age of the 3222 individuals in the safety population was 55·0 years,

Discussion

In this study, vemurafenib was fairly well tolerated and the most frequently reported adverse events were rash, arthralgia, fatigue, photosensitivity, alopecia, and nausea; 93% of the participants had adverse events of grade 1 or 2 and 46% had grade 3 or 4 (table 2). Overall, 95% of patients had at least one adverse event (table 2). The adverse events were consistent with toxicity reported in the BRIM-2 and BRIM-3 registration trials.6, 7, 15 Notably, the incidence of cutaneous squamous cell

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