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The European Medicines Agency review of vemurafenib (Zelboraf®) for the treatment of adult patients with BRAF V600 mutation-positive unresectable or metastatic melanoma: Summary of the scientific assessment of the Committee for Medicinal Products for Human Use
European Journal of Cancer, 7, 49, pages 1654 - 1661
The applicant company Roche Registration Ltd. submitted to the European Medicines Agency (EMA) an application for marketing authorisation for vemurafenib.
Vemurafenib is a low molecular weight, orally available, inhibitor of oncogenic V600 BRAF serine–threonine kinase. Mutations in the BRAF gene which substitute the valine at amino acid position 600 constitutively activate BRAF proteins, which will drive cell proliferation in the absence of growth factors.
Results from a phase 3 trial (N = 675) comparing vemurafenib 960 mg twice daily (taken either with or without food) to standard treatment dacarbazine (DTIC) in patients with BRAF V600E mutation-positive unresectable or metastatic melanoma were submitted. The study met its primary efficacy objective after an interim analysis of overall survival. Patients were allowed to cross-over to the experimental arm following disclosure of the study results after the first interim analysis. In the update of the analysis, the median overall survival (OS) was 9.9 months versus 13.2 months for DTIC and vemurafenib, respectively (HR = 0.67; 95% confidence interval (CI): 0.54, 0.84; cut-off 3 October 2011). Based on the updated analysis, the CHMP concluded that a survival benefit over DTIC had been convincingly demonstrated, in the overall population. The follow-up was considered sufficiently mature with close to 50% of the events observed.
The most common side effects (affecting more than 30% of patients) in vemurafenib treated patients included arthralgia, fatigue, rash, photosensitivity reaction, nausea, alopecia and pruritus. Some patients treated with vemurafenib developed cutaneous squamous cell carcinoma which was readily treated by local surgery.
The objective of this paper is to summarise the scientific review of the application leading to regulatory approval in the European Union (EU). The full scientific assessment report and product information, including the Summary of Product Characteristics (SmPC), are available on the EMA website ( www.ema.europa.eu ).
Keywords: Vemurafenib, Melanoma, EMA, European Medicines Agency.
In Europe, approximately 26,100 males and 33,300 females are diagnosed annually with melanoma, and 8300 males and 7600 females die from the disease every year. 1 About 20% of patients diagnosed with melanoma develop distant metastases and for patients with unresectable or metastatic disease, the prognosis remains poor with a median survival of about 6–9 months, 1 year survival rate of 25.5% and 5-year survival rate lower than 15%.2, 3, and 4 Dacarbazine (DTIC) has been widely used as standard first line treatment of patients with metastatic melanoma, despite modest activity. 5 Clinical trials with DTIC have shown low response rates ranging from 11–25%, low rate of complete responses and of short duration (3–6 months) and a median survival time of 4.5 to 6 months.6, 7, and 8 Recently, the immunotherapeutic agent ipilimumab (Yervoy®), a human monoclonal antibody against CTLA-4, was approved in the EU for patients who have received prior therapy for metastatic melanoma. 9
The applicant company Roche Registration Ltd. submitted to the European Medicines Agency (EMA) an application for Marketing Authorisation for vemurafenib, a V600 BRAF serine–threonine kinase inhibitor. The scientific review was conducted by the Committee of Medicinal Products for Human Use (CHMP). The CHMP recommended the granting of a marketing authorisation for vemurafenib based on a positive benefit–risk balance. The European Commission issued a marketing authorisation on 17/02/2012 for the treatment of adult patients with BRAF V600 mutation-positive unresectable or metastatic melanoma.
2. Non-clinical aspects and clinical pharmacology
Vemurafenib is a low molecular weight, orally available, inhibitor of oncogenic BRAF V600 as well as members of the RAF kinase family (ARAF, BRAF and CRAF). Its mechanism of action has been assessed both in wild type (BRAF WT) and in mutated BRAF models. In cells expressing BRAF V600E, BRAF V600D and BRAF V600R mutated proteins, vemurafenib inhibited both phosphorylated ERK (pERK) and pMEK in a dose-dependent manner. The inhibition of tumour growth and tumour regression activity in BRAF V600E mutant xenograft tumours was observed in a dose-dependent manner in in vivo models. Interestingly, in vitro vemurafenib induced rather than inhibited ERK or MEK phosphorylation of cells expressing BRAF WT proteins. These findings were replicated in xenograft models, where treatment with vemurafenib showed no inhibition of tumour growth against BRAF WT compared to BRAF V600E mutant xenograft tumours in mice. Upregulation of pERK might be a potential mechanism by which vemurafenib stimulates tumour growth. 10
In humans, vemurafenib was highly protein bound (>99%) and appeared to be a P-glycoprotein (Pgp) but not an organic anion transport protein 1B1 and B3 (OATP1B1, OATP1B3) substrate. The possible effect of vemurafenib on other transporters (e.g. BCRP) is currently unknown. The effect of food on absorption of vemurafenib was not determined at the time of marketing authorisation. The recommended dose is 960 mg (4 tablets of 240 mg) twice daily. The first dose is to be taken in the morning and the second dose is to be taken approximately 12 h later in the evening. Each dose in the morning/evening should always be taken in the same manner i.e. either with or without a meal. A food effect study is ongoing to investigate concomitant intake of food and absorption of vemurafenib (study NP25396, NCT01264380).
Vemurafenib at 960 mg twice daily was absorbed with a median time to reach peak plasma concentration (Tmax) of approximately 4 h, its elimination was slow and population pharmacokinetic data indicated a half-life of approximately 50 h. The majority of vemurafenib-related material (94%) was recovered in faeces, and <1% in urine. Therefore biliary excretion of unchanged compound may be an important route of elimination. However, due to the unknown absolute bioavailability, the importance of hepatic and renal excretion for the clearance of parent vemurafenib is currently uncertain.
Pharmacokinetic studies showed that vemurafenib inhibited CYP1A2 enzyme. Vemurafenib was found to induce CYP3A4 after midazolam co-administration and thus, may decrease the plasma exposure of substances predominantly metabolized by CYP3A4, e.g. contraceptive pill. Vemurafenib induced CYP2B6 in vitro at low concentration. It is unknown whether vemurafenib at a plasma level of 100 μM observed in patients at steady state (approximately 50 μg/ml) may decrease plasma concentrations of concomitantly administered CYP2B6 substrates, such as antidepressants like bupropion.
Exposure-dependent QT prolongation was observed in an uncontrolled, open-label phase II study in previously treated patients with metastatic melanoma (NCT00949702, see below), although there were no such findings in the non-clinical data. The management of symptomatic adverse drug reactions or QTc prolongation may require dose reduction, temporary interruption and/or treatment discontinuation, as indicated in the SmPC.
There were no data in children, renal impaired or liver impaired patients submitted in the application. The CHMP requested the applicant to study the latter two special populations in post-authorisation studies.
3. Clinical efficacy
The company submitted one phase 3 study and a single arm phase 2 study. 11 Both studies recruited exclusively patients with BRAF V600E positive metastatic melanoma using the COBAS 4800 BRAF V600 test, which can assess the BRAF mutation status from DNA isolated from formalin-fixed, paraffin-embedded (FFPE) tumour tissue. The test was designed to detect the predominant BRAF V600E mutation with high sensitivity (down to 5% V600E sequence in a background of wild-type sequence from FFPE-derived DNA). Non-clinical and clinical studies with retrospective sequencing analyses had shown that the test also detects the less common BRAF V600D mutations and V600K mutations with lower sensitivity. Both studies evaluated the recommended dose of 960 mg twice daily taken orally, either with or without food.
3.1. Pivotal study BRIM-3 (NCT01006980)
BRIM-3 was a randomised, active control, open label, multicentre study comparing vemurafenib monotherapy with DTIC in patients that were tested positive for the mutant BRAF T1799A (V600E) gene. Patients included in the trial had confirmed metastatic melanoma (unresectable stage IIIC or stage IV), had received no prior systemic anti-cancer therapy for advanced disease and a BRAF V600E-positive mutation tumours confirmed by the COBAS test before the start of the treatment. Patients were randomised to receive vemurafenib (337 patients) at a dose of 960 mg twice daily or DTIC (338 patients) administered intravenously 1000 mg/m2 on day 1 every 3 weeks. Selection of the phase III dose was based on non-clinical data and clinical efficacy and safety observed in the phase I study, PLX06-02 (NCT00405587). In this study, dose limiting toxicities primarily Grade 3 rash and Grade 3 fatigue, were observed in four patients at 1120 mg twice a day (bid). Therefore, the maximum tolerated dose of 960 mg bid, representing the approximate midpoint between 720 mg bid and 1120 mg bid, was selected for further clinical development.
Overall survival (OS) and progression-free survival (PFS) by local evaluation were the two co-primary efficacy endpoints. The stratification factors at randomisation were geographical region (North America, Western Europe, Australia/New Zealand, others), ECOG performance status (0 or 1), stage (unresectable/IIIC, M1a, M1b, M1c stage) and serum lactate dehydrogenase (LDH) normal versus LDH elevated.
A total of 675 patients were randomised. The baseline demographics and disease characteristics were well balanced between the two treatment arms ( Table 1 ). In terms of V600 BRAF mutation status, 79% and 70% of patients had confirmed V600E mutation-positive tumours, for vemurafenib and DTIC, respectively. Out of the patients that had tumours that were tested for non-V600E mutations, 43% and 27% of patients were V600K mutation-positive for vemurafenib and DTIC, respectively.
N = 338
N = 337
|BRAF mutation status by Sanger|
|Non-V600E||33 (30%)||23 (21%)|
|V600E||76 (70%)||88 (79%)|
|Non-V600E BRAF mutation by Sanger|
|No Sequence||17 (52%)||10 (43%)|
|V600K||9 (27%)||10 (43%)|
|WT||6 (18%)||2 (9%)|
Percentages are based on n (number of valid values). Percentages not calculated if n < 10. V600E2: rare 2-base change that results in V600E.
At the pre-specified interim analysis of OS (cut-off 30 December 2010), a significant difference in OS (unstratified log-rank p < 0.0001; HR = 0.37; 95% Confidence interval (CI): 0.26, 0.55) was observed. Following Data Safety Monitoring Board (DSMB) recommendation, those results were released in January 2011 and the study was modified to allow DTIC patients to cross-over to receive vemurafenib. Due to the very short follow-up, the CHMP requested an updated analysis of efficacy as there were concerns related to possible differential activity in patients with rapidly versus more slowly progressive disease. It was acknowledged that a precise estimate of the long-term effect on OS associated with vemurafenib would be difficult to estimate due to the early interim analysis and subsequent cross-over. In the update of the OS analysis, the median OS was 9.9 months versus 13.2 months for DTIC and vemurafenib, respectively (HR = 0.67; 95% CI: 0.54, 0.84; cut-off 3 October 2011), and 9.6 months versus 13.2 months censoring at the date of cross-over (HR = 0.62; 95% CI: 0.49, 0.77; Fig. 1 ). Based on the updated analysis, the CHMP concluded that a survival benefit over DTIC had been convincingly demonstrated, in the overall population. Overall, the cross-over was limited, the follow-up was considered sufficiently mature with close to 50% of the events observed and further follow-up results were consistent ( Table 2 ).
|Cut-off dates||Treatment||Number of deaths (%)||Hazard ratio (95% CI)||Number of cross-over patients (%)|
|December 30, 2010||dacarbazine||75 (22)||0.37 (0.26, 0.55)||0 (not applicable)|
|March 31, 2011||dacarbazine||122 (36)||0.44 (0.33, 0.59) a||50 (15%)|
|October 3,2011||dacarbazine||175 (52)||0.62 (0.49, 0.77) a||81 (24%)|
|February 1, 2012||dacarbazine||200 (59)||0.70 (0.57, 0.87) a||83 (25%)|
a Censored results at time of cross-over.
Non-censored results at time of cross-over: March 31: HR (95% CI) = 0.47 (0.35, 0.62); October 3: HR (95% CI) = 0.67 (0.54, 0.84); February 1: HR (95% CI) = 0.76 (0.63, 0.93).
At the time of the interim OS analysis, median PFS was 1.6 months versus 5.3 months for DTIC and vemurafenib, respectively (HR = 0.26; 95% CI: 0.20, 0.33). Also the PFS analysis was considered immature and an update was requested. At the 1st February 2012 cut-off, median PFS was 1.6 months versus 6.9 months for DTIC and vemurafenib, respectively (HR = 0.41; 95% CI: 0.35, 0.49 without censoring at cross-over; Fig. 2 ). At the time of the interim OS analysis, the response rate was 5.5% (95% CI: 2.8%, 9.3%) versus 48.4% (95% CI: 41.6%, 55.2%) for DTIC and vemurafenib, respectively. Vemurafenib was associated with a favourable effect on OS in the subgroup of patients with tumours with the V600E mutation (N = 164; HR = 0.58; 95% CI: 0.33, 1.02) and in the subgroup of patients with tumours with other activating V600 BRAF mutations (N = 56; HR = 0.44; 95% CI: 0.17, 1.15; Fig. 3 ).
3.2. Supportive study: BRIM-2 (NCT00949702)
This was a single-arm, multi-centre, phase II study of continuous oral dosing of vemurafenib in previously treated patients with metastatic melanoma. A total of 132 patients were enrolled and treated with vemurafenib at the dose of 960 mg twice daily. The best overall response rate (BORR) was 52% with a median duration of response of 6.5 months, as per independent review committee (IRC) evaluation.
4. Clinical safety
The safety database included 866 patients treated in pharmacology studies (84 patients), phase 1 (32 patients), one phase 2 (132 patients) and one randomised phase 3 study (618 patients). The most frequently reported adverse drug reactions (ADRs, all grades) with vemurafenib were arthralgia, fatigue, rash, photosensitivity reaction, nausea, alopecia and pruritus, the majority of which were grade 1–2. The most common adverse events (AEs) ⩾ Grade 3 (based on NCI CTC v4.0) in the vemurafenib group were squamous cell carcinoma (SCC) of skin (11%) and rash (8%) while the most common in the DTIC group were neutropenia (9%) and decreased neutrophil count (4%). Treatment-related serious adverse events (SAEs) were reported by 26% of vemurafenib patients and 5% of DTIC patients.
There was one patient in the vemurafenib-treated group who developed Stevens–Johnson Syndrome: the event was considered related to vemurafenib by the investigator and resolved when vemurafenib was discontinued.
Cutaneous SCC was reported in patients treated with vemurafenib with an incidence across studies of approximately 20%. Cutaneous SCC usually occurred early in the course of treatment with a median time to the first appearance of 7 to 8 weeks. Approximately 33% of patients experienced more than one event, with median time between occurrences of 6 weeks. The majority of the excised lesions reviewed by an independent central dermatopathology laboratory were classified as SCC-keratoacanthoma subtype or with mixed-keratoacanthoma features (52%). Patients aged ⩾65 years had approximately 2.5- to 5-times greater risk of developing cutaneous SCC compared to those <65 years of age.
Rash AEs were reported in 202 patients (60%) in the vemurafenib group compared to 10 patients (4%) in the DTIC group. Most rash AEs were Grade 1 and were considered treatment-related by the investigator. None resulted in discontinuation from treatment but about 54 of 250 events (22%; in the vemurafenib group) led to dose modification or interruption. Photosensitivity AEs were reported in 124 patients (37%) in the vemurafenib group and 10 patients (4%) in the DTIC group in the pivotal trial.
Another ADR of interest was the prolongation of cardiac repolarisation or arrhythmia which occurred in 28 patients (8%) in the vemurafenib group and 16 patients (6%) in the DTIC group in the phase III study. Two patients (1.5%) developed treatment-emergent absolute QTc values >500 ms (Grade 3), and only one patient (0.8%) exhibited a QTc change from baseline of >60 ms. Liver function abnormalities were reported in 18% of vemurafenib patients compared to 5% in DTIC-treated patients in the pivotal study. Most of the liver function abnormalities in patients treated with vemurafenib were grade <3 and the median time to first onset was 3 to 6 weeks. Treatment withdrawal due to adverse events was required in 6% and 4% of patients in the vemurafenib and in the DTIC group, respectively, whereas dose modification was required for 38% and 16% of patients in the vemurafenib and the DTIC group, respectively.
Identified risks, such as cuSCC, liver injury or QT prolongation, will be addressed both as a part of the pharmacovigilance activities and cumulative reviews in the scheduled periodic safety update reports. Additional pharmacovigilance activities will include explorative research studies (a prospective, observational safety study and an open-label, multicentre study to assess the safety of vemurafenib in patients with metastatic melanoma).
5. Discussion and benefit–risk assessment
Interim analyses are routinely employed in oncology trials to monitor safety, assess ‘futility’ and to consider whether there is sufficient evidence of efficacy to stop the trial early. The timing, objectives and conduct of interim analyses designed to stop the trial early for demonstrated efficacy pose a number of challenges. Datasets need to be sufficiently mature to allow robust conclusions to be drawn about the ITT trial population and about subgroups of particular importance (internal consistency). Additionally, one-way cross-over to the experimental arm after progression is likely to hamper any subsequent comparisons in terms of OS and other long-term secondary endpoints. Thus, this type of cross-over should generally be avoided in order to meet the objectives of the trial. If nevertheless it is considered necessary, there should be sufficient confidence that the available data in terms of PFS, OS, and any other important secondary endpoints will be convincing enough from a scientific and regulatory point of view to meet the objectives of the trial and to ensure that adequate conclusions can be drawn.
The initial application for vemurafenib was based on the results of an interim analysis of efficacy. Due to the very short follow-up, the applicant company was requested to submit further updated OS and PFS analyses. These analyses have been submitted and, as expected, mature OS and PFS data showed a less pronounced treatment effect. Nevertheless, in the absence of massive cross-over, the OS data were considered interpretable. In conclusion, the pivotal study has shown convincingly a clinically relevant effect of vemurafenib for OS and PFS.
The adverse events reported were adequately described and were considered acceptable. One issue of concern was the observed higher incidence of squamous cell carcinoma of the skin in patients treated with vemurafenib. A risk minimisation strategy was requested directed at treating physicians to ensure that cutaneous SCC is an identified risk which can be captured early and promptly treated. Thus it was concluded that the benefits of vemurafenib-treatment in melanoma patients harbouring tumours with V600 mutations outweighed the risks and that approval throughout the European Union should be recommended for vemurafenib monotherapy for the treatment of adult patients with BRAF V600 mutation-positive unresectable or metastatic melanoma.
In the phase II and phase III clinical trials, eligible patients were identified using a real-time polymerase chain reaction assay (the COBAS® 4800 BRAF V600 Mutation Test). This test had the mandatory conformity mark for products placed on the market in the European Economic Area (CE marking) and is used to assess the BRAF mutation status of DNA isolated from formalin-fixed, paraffin-embedded (FFPE) tumour tissue. It was designed to detect the predominant BRAF V600E mutation with high sensitivity. Non-clinical and clinical studies with retrospective sequencing analyses have shown that the test also detects the less common BRAF V600D mutations and V600K mutations with lower sensitivity. Of the specimens available from the non-clinical and clinical studies (n = 467) that were mutation-positive by the COBAS test and additionally analysed by sequencing, no specimen was identified as being wild type by both Sanger and 454 sequencing.
A total of 19 patients out of 220 whose tumours were analysed by retrospective sequencing were reported to have BRAF V600K mutation-positive melanoma in the BRIM-3 study. Although limited by the low number of patients, efficacy analyses among these patients with V600K-positive tumours suggested treatment benefit of vemurafenib in terms of OS, PFS and BORR. No data were available in patients with melanoma harbouring BRAF V600 mutations other than V600E and V600K. However, the CHMP considered clinical benefit had been demonstrated in the broader population of patients with melanoma with any substitution at the valine position 600 in the BRAF protein and concluded that there was enough evidence to support a broader indication of “V600 mutation” and not to restrict the indication to BRAF V600E patient population. Conversely, there appeared to be no benefit in patients whose tumours are BRAF wild-type. Therefore, before taking vemurafenib, patients must have BRAF V600 mutation-positive tumour status confirmed by a validated test.
There was uncertainty in the knowledge of the long-term benefit of vemurafenib in melanoma patients that harbour the BRAF V600 mutation and the impact of prognostic factors. This, however, did not affect the observed clinical benefit for patients in OS and the positive benefit-risk of vemurafenib in the proposed indication.
Further clarification has been requested on the effect of food on the bioavailability of vemurafenib. The food effect had not been fully investigated prior to the start of the phase III study and the data had been requested as part of risk management plan measures. The results from the food effect study NP25398 showed an increased relative bioavailability of a single 960 mg dose of vemurafenib with intake of high fat meal. Thus, it is recommended to take vemurafenib with or without food, but consistent intake of both daily doses on an empty stomach should be avoided as it may lead to significantly lower steady state exposure than consistent intake of vemurafenib with or a short time after a meal. There is also some uncertainty with regard to patients with hepatic impairment. Given that vemurafenib is metabolised by the liver, this is important missing information. There is a planned study to address this safety issue for which a clinical study report is due on 31/08/2017.
The EMA will review new safety and efficacy information about vemurafenib in the post-marketing phase. The most current information on this medicinal product is available on the EMA website ( www.ema.europa.eu ).
This publication is a summary of the European Public Assessment Report, updated analyses of efficacy submitted by the applicant company in the post-marketing phase, the summary of product characteristics and other product information as published on the EMA website ( www.ema.europa.eu ). For the most current information on this marketing authorisation, please refer to the EMA website. The authors of this paper remain solely responsible for the opinions expressed in this publication.
Conflict of interest statement
The following authors declare no conflict of interest and that they have no financial and personal relationships with people or organisations that could inappropriately influence (bias) the work submitted for publication: Tomas Salmonson, Barbara vanZieten-Boot, Bertil Jonsson, Serena Marchetti, Silvy da Rocha Dias and Francesco Pignatti. The following authors declare the following conflict of interest: Rosa Giuliani has done consultancy work for Astra Zeneca, Roche and Sanofi-Aventis and has been involved as a non-principal investigator for the following companies Sanofi-Aventis, Nerviano Medical Science, Medivation, Wyeth, GPC Biotech AG, Novartis, Roche, GlaxoSmithKline, Cougar – Johnson&Johnson, Pfizer. Jan Schellens has been involved in a strategic advisory role for Astra Zeneca, Eisai and GlaxoSmithKline and has been involved as a non-principal investigator for KuDos Pharmaceuticas, Bayer, GlaxoSmithKline, Merck Sharp & Dome, KWF, Roche, Genentech, Astra Zeneca, Novartis, Eisai, Clavis Pharma ASA. Dr Schellens also holds a number of patents (1. Taxane Formulation and Taxane/CYP3A4 Inhibitor Combination 2. Taxane Formulations and Taxane Formulations Prepared By Spray Drying and 3. Taxane Formulations Prepared By Spray Drying).
The scientific assessment summarised in this report is based on important contributions from the rapporteur and co-rapporteur assessment teams, CHMP members and additional experts following the application for a marketing authorisation from the company.
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a European Medicines Agency, London, United Kingdom
b Medical Products Agency, Uppsala, Sweden
c Medicines Evaluation Board, Den Haag, The Netherlands
d Department of Clinical Pharmacology, The Netherlands Cancer Institute, Antoni van Leeuwenhoek Ziekenhuis, Amsterdam, The Netherlands
e Department of Pharmaceutical Sciences, Utrecht University, Utrecht, The Netherlands
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