DRUG EVALUATION For reprint orders, please contact: [email protected]
Vemurafenib for the treatment of BRAF mutant metastatic melanoma
Juan Martin-Liberal1 & James Larkin*,1
ABSTRACT Vemurafenib was the first selective BRAF inhibitor licensed in cancer. It is indicated for the treatment of patients affected by advanced melanoma with BRAF V600 mutation. It has shown successful results in terms of efficacy together with a favorable toxicity profile. Other compounds such as the BRAF inhibitor dabrafenib and the immunotherapeutic agent ipilimumab are also approved in the same group of patients. This article reviews the chemistry, pharmacokinetics, pharmacodynamics and clinical development of vemurafenib. Moreover, its efficacy and toxicity are compared with dabrafenib and ipilimumab. A number of trials with vemurafenib alone or in combination with other drugs are also analyzed. These trials will determine the role of vemurafenib in the treatment of BRAF mutant melanoma in forthcoming years. The management of malignant melanoma is one of the most complex challenges in oncology. In addition, its incidence has significantly increased in recent years and it is currently the second most frequent malignancy in men and women under 40 years of age [1] . Each year approximately 200,000 new cases are diagnosed worldwide and the number of deaths related to melanoma is around 65,000 [2] . Moreover, it has been classically considered as a poor-prognosis condition. Until 2011 the only available drugs for the treatment of metastatic melanoma were dacarbazine (DTIC) and IL-2 [3] . These compounds had limited activity in the general population, with around 10% response rates (RRs) and response durations generally short [4,5] . With such scarce therapeutic options, median survival of patients affected by metastatic melanoma was around 6–9 months [6] . However, the identification of somatic gene mutations responsible for driving the malignant phenotype of melanoma and the development of drugs able to target proteins with those mutations has meant a major advance in the treatment of this disease [7] . For instance, the blockage of mutated BRAF, one of the key effectors of the MAPK signaling pathway, has achieved very successful results [8] . The MAPK pathway is a signaling network essential for normal cellular processes [9] but its abnormal functioning caused by aberrations in BRAF is directly involved in melanoma pathogenesis [10] . One of the first drugs developed to target mutant BRAF was vemurafenib. It was approved by the US FDA in 2011 [11] and by the EMA in 2012 [12] for the treatment of patients with unresectable or metastatic melanoma with BRAF V600 mutations (only V600E mutation in the case of FDA), the most frequent of the BRAF aberrations [13] . This drug, together with other targeted therapies and immunotherapeutic agents, has dramatically changed the landscape of the treatment of metastatic melanoma in recent years [14] . The most mature data from the BRIM3 registration study indicate a median overall survival (OS) of BRAF mutant melanoma patients treated with vemurafenib of 13.6 months in comparison with 9.7 months for DTIC, the data being censored at crossover [15] .
KEYWORDS
• BRAF • chemistry • dabrafenib • ipilimumab • MAPK • MEK • melanoma • pharmacodynamics • pharmacokinetics • vemurafenib
The Royal Marsden Hospital, Fulham Road, London, SW3 6JJ, UK *Author for correspondence: Tel.: +44 20 7811 8576; Fax: +44 20 7811 8103; [email protected] 1
10.2217/FON.14.252 © 2015 Future Medicine Ltd
Future Oncol. (2015) 11(4), 579–589
part of
ISSN 1479-6694
579
Drug Evaluation Martin-Liberal & Larkin In this article, the clinical development of vemurafenib will be extensively reviewed. Also, a perspective of the future role of vemurafenib in the treatment of melanoma in forthcoming years will be provided. Molecular characteristics of vemurafenib Vemurafenib is a compound structurally closely related to its precursor PLX4720 [16] , whose chemical structure is propane-1-sulfonic acid (3-[5-chloro-1H-pyrrolo(2,3-b)pyridine-3-carbonyl]-2,4-difluoro-phenyl)-amide (Figure 1) [17] . PLX4720 is able to inhibit the kinase activity in vitro of the most common BRAF mutation, the substitution of glutamic acid for valine at codon 600 of exon 15 (V600E), at tenfold lower concentrations than wild-type BRAF [17] . Its reversible and highly selective derivative vemurafenib binds the ATP-binding domain of the mutant BRAF monomer [18] , leading to decreased cellular proliferation through reductions of phosphorylated ERK, a component of the MAPK pathway downstream from BRAF, and cyclin D1 [19] . The effect of vemurafenib in cells that do not harbor mutation in BRAF might be the contrary: it can potentially activate the MAPK pathway in a RAS-dependent manner by inducing dimerization and membrane localization of the wild-type RAF isoforms [20,21] . This feature has direct implications in the profile of side effects of vemurafenib. Pharmacokinetics & pharmacodynamics The first-in-human clinical trial of vemurafenib included pharmacokinetics and pharmacodynamics studies [23] . Pharmacokinetics analyses were conducted on days 1 and 15 of treatment and plasma samples were taken every 4 weeks. Since the initial serum levels detected were lower than predicted in preclinical models to be effective, a microprecipitated bulk powder formulation with higher bioavailability was developed and newly enrolled patients and patients
O O S N H
O F N
N H
Figure 1. Chemical structure of vemurafenib. Data taken from [22].
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Future Oncol. (2015) 11(4)
Clinical efficacy ●●Phase I study
F CI
who had been receiving the initial crystalline formulation were switched to the new formulation. Exposure to vemurafenib was found to be proportionally increased with the dose for doses from 240 mg twice daily (b.i.d.) to 960 mg b.i.d. At the recommended dose (RD) of 960 mg b.i.d., the mean area under the plasma concentration–time curve over a 24-h period (AUC 0–24 ) was 1741 ± 639 μM × h and the mean maximum concentration at steady state was 86 ± 32 μM. At day 15, the mean level of vemurafenib was six- to nine-times the mean level observed at day 1. Its half-life was reported to be 50 h (range: 30–80) [23] . For the pharmacodynamics study, some patients had a tumor biopsy from a subcutaneous lesion or a superficial lymph node before starting on vemurafenib and on day 15. Biopsies were taken from different lesions except in one case. Immunohistochemistry (IHC) for phosphorylated ERK, cyclin D1 and Ki-67 performed in the sequential biopsies showed inhibition of the MAPK pathway at the RD. Thus, phosphorylated ERK, cyclin D1 and Ki-67 were found to be significantly reduced at day 15 compared with baseline [23] . In a subsequent Phase II trial, a similar pharmacodynamic study was conducted [24] . A total of 32 out of 132 patients enrolled in the study [24%] had paired biopsies at baseline and at day 15. The effects of vemurafenib on the MAPK pathway were assessed by IHC of phosphorylated ERK and MEK, another key effector of the MAPK signaling network. Also, effects on cell cycle regulation and proliferation were determined by IHC of cyclin D1, p27 and Ki-67. After 15 days of vemurafenib, phosphorylated ERK and MEK were decreased, more strongly in the case of ERK. Cyclin D1 and Ki-67 levels were also significantly reduced, whereas p27 was found increased indicating a reduction in tumor cell proliferation [25] .
The first clinical study with vemurafenib was published in 2010. The trial had two phases: a dose escalation phase to find the RD for the Phase II trial in which patients were enrolled regardless their BRAF mutational status, and an extension phase designed to preliminary assess the efficacy of vemurafenib in BRAF V600E mutant advanced melanoma patients. In total, 55 patients with advanced solid tumors were
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Vemurafenib for the treatment of BRAF mutant metastatic melanoma enrolled in the dose escalation phase, and 32 additional patients were included in the extension phase. Among the 55 patients enrolled in the dose-finding phase, there were 49 affected by melanoma. In the dose escalation phase, no responses were observed with 160 mg b.i.d. However, of 16 patients with BRAF V600E mutated tumors, partial (PR) or complete response (CR) were seen in one out of one, two out of four, four out six and four out of five cases at doses 240 mg b.i.d., 320 or 360 mg b.i.d., 720 mg b.i.d. and 1120 mg b.i.d., respectively. Overall, the RR was 69% (11 out of 16 patients) with response duration ranging from 2 to more than 18 months. No responses were seen in the five melanoma patients without BRAF mutation included in this phase [23] . In the extension phase, focused on advanced melanoma patients harboring the BRAF V600E mutation, all participants were treated at the RD of 960 mg b.i.d. The RR was 81% (26 out of 32 patients), with two patients achieving CR and 24 patients achieving PR. Patients responded to vemurafenib even if they had elevated lactate dehydrogenase, a marker of bad prognosis in melanoma (ten out of 13 cases), or if they had received more than one previous line of treatment (11 out of 16 patients). Improvement of symptoms in patients with symptomatic disease was reported after just 1 or 2 weeks of treatment. Estimated median progression-free survival (PFS) was more than 7 months [23] . ●●Phase II studies
After establishing the RD of vemurafenib at 960 mg b.i.d., 132 patients with previously treated BRAF V600 mutant advanced melanoma were enrolled in a Phase II trial. The aim of the study was to evaluate the efficacy of vemurafenib by determining the overall RR, duration of response and OS. With a median followup of 12.9 months (range: 0.6–20.1), overall RR by independent review committee was 53%. In total, 38 patients (29%) had stable disease (SD) as best response, 62 patients (47%) achieved PR and in 8 patients (6%) CR was reported. The rate of primary progressive disease was 14% (18 patients). Interestingly, patients with substitution of valine for lysine at codon 600 of exon 15 (V600K) of their tumors (the second most common BRAF mutation in melanoma) [26] also benefited from vemurafenib: from a total of ten patients, four had PR, three had SD, two
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Drug Evaluation
had progressive disease and in one case response could not be assessed. In the overall population of the study, median duration of response was 6.7 months and median PFS was 6.8 months. The 6-month PFS rate was 56%. Regarding OS, the median was 15.9 months and the rate at 6, 12 and estimated at 18 months was 77, 58 and 43%, respectively [24] . The appearance of brain metastases is a frequent and challenging issue in patients with melanoma. In this subset of patients, vemurafenib has also demonstrated to be effective. An openlabel Phase II pilot trial was conducted in BRAF V600 mutation positive metastatic melanoma patients with nonresectable, previously treated brain metastases. In ten out of the 24 patients enrolled (42%), PR at both intracranial and extracranial sites was achieved. In addition, nine patients (38%) had SD and seven out of 19 patients (37%) with measurable intracranial disease achieved more than 30% intracranial tumor regression. The reported confirmed intracranial PR rate was 16%. Other signs of efficacy observed were reduced need for steroids and improvement in performance status. The median PFS reported was 3.9 months and median OS was 5.3 months [27] . Vemurafenib efficacy in Phase I and II trials is summarized in Table 1. ●●Phase III study
Encouraging results observed in the Phase II study led to a comparative Phase III trial. Thus, Chapman et al. conducted a Phase III randomized trial that compared vemurafenib with DTIC in treatment-naïve patients affected by metastatic melanoma harboring the BRAF V600E mutation. A total of 675 patients were randomized to receive either vemurafenib 960 mg b.i.d. or DTIC 1000 mg/m 2 intravenously (iv.) every 3 weeks and the trial was designed to assess OS and PFS as primary end points. At the time of the report of the results of the study, 439 patients were evaluable for tumor response on the basis of having undergone randomization at least 14 weeks before clinical cutoff date. Among the 219 patients in the vemurafenib arm, 106 (48%) achieved at least PR (104 PR and 2 CR) whereas the RR in the DTIC group was only 5%. This difference was statistically significant (p < 0.001 by the chi-square test). PFS was evaluated in 549 patients, the median being 5.3 months in the vemurafenib group and 1.6 months in the DTIC group. This superiority was observed in
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Drug Evaluation Martin-Liberal & Larkin Table 1. Summary of vemurafenib Phase I and II trials. Phase
Response rate
Progression-free survival (median)
Phase I, n = 87
Overall survival Toxicity (most frequent) (median)
69% (dose-escalation More than phase), 81% 7 months (extension phase) Phase II, n = 132 53% 6.8 months
–
Phase II brain metastases (pilot study) n = 24
5.3 months
42%
3.9 months
15.9 months
Squamous cell carcinomas or keratoacanthomas (21%), arthralgia (18%), skin rash (15%), nausea (10%), fatigue (8%), photosensitivity (8%) Arthralgia (53%), photosensitivity (49%), rash (45%), fatigue (40%), alopecia (36%) and cutaneous squamous cell carcinomas or keratoacanthomas (26%) Arthralgia (38%), seizure (25%), alopecia (21%), diarrhea (21%), dizziness (21%), muscular weakness (21%), maculopapular rash (21%), paresthesia (21%), solar dermatitis (21%), vomiting (21%)
all analyzed subgroups. In a total of 672 patients, OS was assessed. Immature data showed 84 versus 64% OS at 6 months in favor of vemurafenib. Again, survival in the vemurafenib arm was significantly higher than in the DTIC arm in every subgroup evaluated. Vemurafenib was associated with a relative reduction of 63% in the risk of death and of 74% in the risk of either death or disease progression, as compared with dacarbazine (p < 0.001 for both comparisons) in a preplanned interim analysis. After such results, crossover to vemurafenib from DTIC was allowed [28] . In 2014, updated survival data censored at crossover were published. Median OS was found to be significantly longer with vemurafenib compared with DTIC: 13.6 months versus 9.7 months (hazard ratio [HR]: 0.70; 95% CI: 0.57–0.87; p = 0.0008). Median PFS was also superior in the vemurafenib patients: 6.9 months versus 1.6 months (HR: 0.38; 95% CI: 0.32–0.46; p < 0.0001). When data were analyzed by BRAF mutation, median OS with vemurafenib in the BRAF V600E group was 13.3 months compared with 10.0 months in the DTIC group (HR: 0.75; 95% CI: 0.60–0.93; p = 0.0085). Patients with BRAF V600K mutation had a median OS of 14.5 months with vemurafenib (33 patients) and 7.6 months with DTIC (24 patients; HR: 0.43; 95% CI: 0.21–0.90; p = 0.024). Median PFS was 5.9 months and 1.7 months, respectively (HR: 0.30; 95% CI: 0.16–0.56; p < 0.0001) [15] . Safety & tolerability During its clinical development, vemurafenib demonstrated to be generally well tolerated with a specific profile of side effects easily manageable in most cases. In the dose finding of the Phase I study, four out of the six patients that received
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Ref. [23]
[24]
[27]
vemurafenib 1120 mg b.i.d. had a dose-limiting toxicity: three patients developed grade 3 skin rash (two of whom also had grade 3 fatigue) and one patient had grade 3 arthralgia. The next lower dose, 960 mg b.i.d., was established as the RD since it was well tolerated by the first six patients who received it. In the extension cohort, 13 patients [41%] required a dose reduction. Overall, the most frequently reported adverse events were squamous cell carcinomas or keratoacanthomas (21%), arthralgia (18%), skin rash (15%), nausea (10%), fatigue (8%) and photosensitivity (8%). Of all the side effects, the majority [89%] were grade 1 or 2. The appearance of new cutaneous carcinomas did not lead to discontinuation of vemurafenib and in most cases the treatment was simple resection. No squamous cell carcinomas in other locations than the skin were reported [23] . The Phase II and III trials published to date showed similar results in terms of safety. In the study by Sosman et al., the most commonly reported adverse events were arthralgia (53%), photosensitivity (49%), rash (45%), fatigue (40%), alopecia (36%) and cutaneous squamous cell carcinomas or keratoacanthomas (26%). In spite of the high incidence of new skin tumors, no mucosal squamous-cell carcinoma or metastases of cutaneous squamous cell carcinoma were observed and only four patients had to discontinue treatment because of toxicity [24] . In the pilot Phase II study specifically addressed to melanoma patients with brain metastases, which primary end-point was safety, vemurafenib was also generally well tolerated. The most frequent adverse events in the total of 24 patients included were arthralgia (38%), seizure (25%), alopecia (21%), diarrhoea (21%), dizziness (21%), muscular weakness (21%), maculopapular rash (21%), paresthesia [21%), solar dermatitis (21%)
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Vemurafenib for the treatment of BRAF mutant metastatic melanoma and vomiting (21%) [27] . Patients enrolled in the randomized Phase III trial experienced a profile of side effects consistent with previous studies: keratoacanthomas or squamous cell carcinomas (20%), arthralgia (18%), rash (18%), fatigue (13%), photosensitivity skin reactions (12%), nausea (8%) and alopecia (8%) were the most reported toxicities. As in earlier clinical trials, all new skin tumors were successfully treated by simple excision [28] . In the updated survival analysis the most frequent grade 3–4 events observed in patients treated with vemurafenib were cutaneous squamous cell carcinomas (19%) and keratoacanthomas (10%), abnormal liver function tests (11%) and skin rash (9%) [15] . Vemurafenib toxicity in Phase I and II trials is summarized in Table 1. Results of an open-label, multicentric study that analyzed the safety of vemurafenib in 3226 patients with metastatic melanoma have recently been published. This representative of routine clinical practice study enrolled patients from 44 different countries over nearly 2 years. Patients with brain metastases, Eastern Cooperative Oncology Group Performance Status (ECO G PS) 2 and increased lactate dehydrogenase were allowed. The most common side effects found were skin rash (49%), arthralgia (39%), fatigue (34%), photosensitivity reaction (31%), alopecia (26%) and nausea (19%), which confirms the safety profile observed in the Phase I, II and III clinical trials. Grade 3 or 4 toxicities such as cutaneous squamous cell carcinomas (12%), skin rash (5%), liver function abnormalities (5%), arthralgia (3%) or fatigue (3%) were seen in 46% of patients. Patients aged 75 years or older reported higher incidence of grade 3 and grade 4 adverse events (59 and 4%, respectively) compared with younger patients (43 and 3%, respectively). A total of 14% of patients required dose reductions because of adverse events, the main reasons being arthralgia (3%) and skin rash (2%). Discontinuation rate attributed to adverse events was 6%, with QTc prolongation (
Vemurafenib for the treatment of BRAF mutant metastatic melanoma
Juan Martin-Liberal1 & James Larkin*,1
ABSTRACT Vemurafenib was the first selective BRAF inhibitor licensed in cancer. It is indicated for the treatment of patients affected by advanced melanoma with BRAF V600 mutation. It has shown successful results in terms of efficacy together with a favorable toxicity profile. Other compounds such as the BRAF inhibitor dabrafenib and the immunotherapeutic agent ipilimumab are also approved in the same group of patients. This article reviews the chemistry, pharmacokinetics, pharmacodynamics and clinical development of vemurafenib. Moreover, its efficacy and toxicity are compared with dabrafenib and ipilimumab. A number of trials with vemurafenib alone or in combination with other drugs are also analyzed. These trials will determine the role of vemurafenib in the treatment of BRAF mutant melanoma in forthcoming years. The management of malignant melanoma is one of the most complex challenges in oncology. In addition, its incidence has significantly increased in recent years and it is currently the second most frequent malignancy in men and women under 40 years of age [1] . Each year approximately 200,000 new cases are diagnosed worldwide and the number of deaths related to melanoma is around 65,000 [2] . Moreover, it has been classically considered as a poor-prognosis condition. Until 2011 the only available drugs for the treatment of metastatic melanoma were dacarbazine (DTIC) and IL-2 [3] . These compounds had limited activity in the general population, with around 10% response rates (RRs) and response durations generally short [4,5] . With such scarce therapeutic options, median survival of patients affected by metastatic melanoma was around 6–9 months [6] . However, the identification of somatic gene mutations responsible for driving the malignant phenotype of melanoma and the development of drugs able to target proteins with those mutations has meant a major advance in the treatment of this disease [7] . For instance, the blockage of mutated BRAF, one of the key effectors of the MAPK signaling pathway, has achieved very successful results [8] . The MAPK pathway is a signaling network essential for normal cellular processes [9] but its abnormal functioning caused by aberrations in BRAF is directly involved in melanoma pathogenesis [10] . One of the first drugs developed to target mutant BRAF was vemurafenib. It was approved by the US FDA in 2011 [11] and by the EMA in 2012 [12] for the treatment of patients with unresectable or metastatic melanoma with BRAF V600 mutations (only V600E mutation in the case of FDA), the most frequent of the BRAF aberrations [13] . This drug, together with other targeted therapies and immunotherapeutic agents, has dramatically changed the landscape of the treatment of metastatic melanoma in recent years [14] . The most mature data from the BRIM3 registration study indicate a median overall survival (OS) of BRAF mutant melanoma patients treated with vemurafenib of 13.6 months in comparison with 9.7 months for DTIC, the data being censored at crossover [15] .
KEYWORDS
• BRAF • chemistry • dabrafenib • ipilimumab • MAPK • MEK • melanoma • pharmacodynamics • pharmacokinetics • vemurafenib
The Royal Marsden Hospital, Fulham Road, London, SW3 6JJ, UK *Author for correspondence: Tel.: +44 20 7811 8576; Fax: +44 20 7811 8103; [email protected] 1
10.2217/FON.14.252 © 2015 Future Medicine Ltd
Future Oncol. (2015) 11(4), 579–589
part of
ISSN 1479-6694
579
Drug Evaluation Martin-Liberal & Larkin In this article, the clinical development of vemurafenib will be extensively reviewed. Also, a perspective of the future role of vemurafenib in the treatment of melanoma in forthcoming years will be provided. Molecular characteristics of vemurafenib Vemurafenib is a compound structurally closely related to its precursor PLX4720 [16] , whose chemical structure is propane-1-sulfonic acid (3-[5-chloro-1H-pyrrolo(2,3-b)pyridine-3-carbonyl]-2,4-difluoro-phenyl)-amide (Figure 1) [17] . PLX4720 is able to inhibit the kinase activity in vitro of the most common BRAF mutation, the substitution of glutamic acid for valine at codon 600 of exon 15 (V600E), at tenfold lower concentrations than wild-type BRAF [17] . Its reversible and highly selective derivative vemurafenib binds the ATP-binding domain of the mutant BRAF monomer [18] , leading to decreased cellular proliferation through reductions of phosphorylated ERK, a component of the MAPK pathway downstream from BRAF, and cyclin D1 [19] . The effect of vemurafenib in cells that do not harbor mutation in BRAF might be the contrary: it can potentially activate the MAPK pathway in a RAS-dependent manner by inducing dimerization and membrane localization of the wild-type RAF isoforms [20,21] . This feature has direct implications in the profile of side effects of vemurafenib. Pharmacokinetics & pharmacodynamics The first-in-human clinical trial of vemurafenib included pharmacokinetics and pharmacodynamics studies [23] . Pharmacokinetics analyses were conducted on days 1 and 15 of treatment and plasma samples were taken every 4 weeks. Since the initial serum levels detected were lower than predicted in preclinical models to be effective, a microprecipitated bulk powder formulation with higher bioavailability was developed and newly enrolled patients and patients
O O S N H
O F N
N H
Figure 1. Chemical structure of vemurafenib. Data taken from [22].
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Future Oncol. (2015) 11(4)
Clinical efficacy ●●Phase I study
F CI
who had been receiving the initial crystalline formulation were switched to the new formulation. Exposure to vemurafenib was found to be proportionally increased with the dose for doses from 240 mg twice daily (b.i.d.) to 960 mg b.i.d. At the recommended dose (RD) of 960 mg b.i.d., the mean area under the plasma concentration–time curve over a 24-h period (AUC 0–24 ) was 1741 ± 639 μM × h and the mean maximum concentration at steady state was 86 ± 32 μM. At day 15, the mean level of vemurafenib was six- to nine-times the mean level observed at day 1. Its half-life was reported to be 50 h (range: 30–80) [23] . For the pharmacodynamics study, some patients had a tumor biopsy from a subcutaneous lesion or a superficial lymph node before starting on vemurafenib and on day 15. Biopsies were taken from different lesions except in one case. Immunohistochemistry (IHC) for phosphorylated ERK, cyclin D1 and Ki-67 performed in the sequential biopsies showed inhibition of the MAPK pathway at the RD. Thus, phosphorylated ERK, cyclin D1 and Ki-67 were found to be significantly reduced at day 15 compared with baseline [23] . In a subsequent Phase II trial, a similar pharmacodynamic study was conducted [24] . A total of 32 out of 132 patients enrolled in the study [24%] had paired biopsies at baseline and at day 15. The effects of vemurafenib on the MAPK pathway were assessed by IHC of phosphorylated ERK and MEK, another key effector of the MAPK signaling network. Also, effects on cell cycle regulation and proliferation were determined by IHC of cyclin D1, p27 and Ki-67. After 15 days of vemurafenib, phosphorylated ERK and MEK were decreased, more strongly in the case of ERK. Cyclin D1 and Ki-67 levels were also significantly reduced, whereas p27 was found increased indicating a reduction in tumor cell proliferation [25] .
The first clinical study with vemurafenib was published in 2010. The trial had two phases: a dose escalation phase to find the RD for the Phase II trial in which patients were enrolled regardless their BRAF mutational status, and an extension phase designed to preliminary assess the efficacy of vemurafenib in BRAF V600E mutant advanced melanoma patients. In total, 55 patients with advanced solid tumors were
future science group
Vemurafenib for the treatment of BRAF mutant metastatic melanoma enrolled in the dose escalation phase, and 32 additional patients were included in the extension phase. Among the 55 patients enrolled in the dose-finding phase, there were 49 affected by melanoma. In the dose escalation phase, no responses were observed with 160 mg b.i.d. However, of 16 patients with BRAF V600E mutated tumors, partial (PR) or complete response (CR) were seen in one out of one, two out of four, four out six and four out of five cases at doses 240 mg b.i.d., 320 or 360 mg b.i.d., 720 mg b.i.d. and 1120 mg b.i.d., respectively. Overall, the RR was 69% (11 out of 16 patients) with response duration ranging from 2 to more than 18 months. No responses were seen in the five melanoma patients without BRAF mutation included in this phase [23] . In the extension phase, focused on advanced melanoma patients harboring the BRAF V600E mutation, all participants were treated at the RD of 960 mg b.i.d. The RR was 81% (26 out of 32 patients), with two patients achieving CR and 24 patients achieving PR. Patients responded to vemurafenib even if they had elevated lactate dehydrogenase, a marker of bad prognosis in melanoma (ten out of 13 cases), or if they had received more than one previous line of treatment (11 out of 16 patients). Improvement of symptoms in patients with symptomatic disease was reported after just 1 or 2 weeks of treatment. Estimated median progression-free survival (PFS) was more than 7 months [23] . ●●Phase II studies
After establishing the RD of vemurafenib at 960 mg b.i.d., 132 patients with previously treated BRAF V600 mutant advanced melanoma were enrolled in a Phase II trial. The aim of the study was to evaluate the efficacy of vemurafenib by determining the overall RR, duration of response and OS. With a median followup of 12.9 months (range: 0.6–20.1), overall RR by independent review committee was 53%. In total, 38 patients (29%) had stable disease (SD) as best response, 62 patients (47%) achieved PR and in 8 patients (6%) CR was reported. The rate of primary progressive disease was 14% (18 patients). Interestingly, patients with substitution of valine for lysine at codon 600 of exon 15 (V600K) of their tumors (the second most common BRAF mutation in melanoma) [26] also benefited from vemurafenib: from a total of ten patients, four had PR, three had SD, two
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Drug Evaluation
had progressive disease and in one case response could not be assessed. In the overall population of the study, median duration of response was 6.7 months and median PFS was 6.8 months. The 6-month PFS rate was 56%. Regarding OS, the median was 15.9 months and the rate at 6, 12 and estimated at 18 months was 77, 58 and 43%, respectively [24] . The appearance of brain metastases is a frequent and challenging issue in patients with melanoma. In this subset of patients, vemurafenib has also demonstrated to be effective. An openlabel Phase II pilot trial was conducted in BRAF V600 mutation positive metastatic melanoma patients with nonresectable, previously treated brain metastases. In ten out of the 24 patients enrolled (42%), PR at both intracranial and extracranial sites was achieved. In addition, nine patients (38%) had SD and seven out of 19 patients (37%) with measurable intracranial disease achieved more than 30% intracranial tumor regression. The reported confirmed intracranial PR rate was 16%. Other signs of efficacy observed were reduced need for steroids and improvement in performance status. The median PFS reported was 3.9 months and median OS was 5.3 months [27] . Vemurafenib efficacy in Phase I and II trials is summarized in Table 1. ●●Phase III study
Encouraging results observed in the Phase II study led to a comparative Phase III trial. Thus, Chapman et al. conducted a Phase III randomized trial that compared vemurafenib with DTIC in treatment-naïve patients affected by metastatic melanoma harboring the BRAF V600E mutation. A total of 675 patients were randomized to receive either vemurafenib 960 mg b.i.d. or DTIC 1000 mg/m 2 intravenously (iv.) every 3 weeks and the trial was designed to assess OS and PFS as primary end points. At the time of the report of the results of the study, 439 patients were evaluable for tumor response on the basis of having undergone randomization at least 14 weeks before clinical cutoff date. Among the 219 patients in the vemurafenib arm, 106 (48%) achieved at least PR (104 PR and 2 CR) whereas the RR in the DTIC group was only 5%. This difference was statistically significant (p < 0.001 by the chi-square test). PFS was evaluated in 549 patients, the median being 5.3 months in the vemurafenib group and 1.6 months in the DTIC group. This superiority was observed in
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Drug Evaluation Martin-Liberal & Larkin Table 1. Summary of vemurafenib Phase I and II trials. Phase
Response rate
Progression-free survival (median)
Phase I, n = 87
Overall survival Toxicity (most frequent) (median)
69% (dose-escalation More than phase), 81% 7 months (extension phase) Phase II, n = 132 53% 6.8 months
–
Phase II brain metastases (pilot study) n = 24
5.3 months
42%
3.9 months
15.9 months
Squamous cell carcinomas or keratoacanthomas (21%), arthralgia (18%), skin rash (15%), nausea (10%), fatigue (8%), photosensitivity (8%) Arthralgia (53%), photosensitivity (49%), rash (45%), fatigue (40%), alopecia (36%) and cutaneous squamous cell carcinomas or keratoacanthomas (26%) Arthralgia (38%), seizure (25%), alopecia (21%), diarrhea (21%), dizziness (21%), muscular weakness (21%), maculopapular rash (21%), paresthesia (21%), solar dermatitis (21%), vomiting (21%)
all analyzed subgroups. In a total of 672 patients, OS was assessed. Immature data showed 84 versus 64% OS at 6 months in favor of vemurafenib. Again, survival in the vemurafenib arm was significantly higher than in the DTIC arm in every subgroup evaluated. Vemurafenib was associated with a relative reduction of 63% in the risk of death and of 74% in the risk of either death or disease progression, as compared with dacarbazine (p < 0.001 for both comparisons) in a preplanned interim analysis. After such results, crossover to vemurafenib from DTIC was allowed [28] . In 2014, updated survival data censored at crossover were published. Median OS was found to be significantly longer with vemurafenib compared with DTIC: 13.6 months versus 9.7 months (hazard ratio [HR]: 0.70; 95% CI: 0.57–0.87; p = 0.0008). Median PFS was also superior in the vemurafenib patients: 6.9 months versus 1.6 months (HR: 0.38; 95% CI: 0.32–0.46; p < 0.0001). When data were analyzed by BRAF mutation, median OS with vemurafenib in the BRAF V600E group was 13.3 months compared with 10.0 months in the DTIC group (HR: 0.75; 95% CI: 0.60–0.93; p = 0.0085). Patients with BRAF V600K mutation had a median OS of 14.5 months with vemurafenib (33 patients) and 7.6 months with DTIC (24 patients; HR: 0.43; 95% CI: 0.21–0.90; p = 0.024). Median PFS was 5.9 months and 1.7 months, respectively (HR: 0.30; 95% CI: 0.16–0.56; p < 0.0001) [15] . Safety & tolerability During its clinical development, vemurafenib demonstrated to be generally well tolerated with a specific profile of side effects easily manageable in most cases. In the dose finding of the Phase I study, four out of the six patients that received
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Ref. [23]
[24]
[27]
vemurafenib 1120 mg b.i.d. had a dose-limiting toxicity: three patients developed grade 3 skin rash (two of whom also had grade 3 fatigue) and one patient had grade 3 arthralgia. The next lower dose, 960 mg b.i.d., was established as the RD since it was well tolerated by the first six patients who received it. In the extension cohort, 13 patients [41%] required a dose reduction. Overall, the most frequently reported adverse events were squamous cell carcinomas or keratoacanthomas (21%), arthralgia (18%), skin rash (15%), nausea (10%), fatigue (8%) and photosensitivity (8%). Of all the side effects, the majority [89%] were grade 1 or 2. The appearance of new cutaneous carcinomas did not lead to discontinuation of vemurafenib and in most cases the treatment was simple resection. No squamous cell carcinomas in other locations than the skin were reported [23] . The Phase II and III trials published to date showed similar results in terms of safety. In the study by Sosman et al., the most commonly reported adverse events were arthralgia (53%), photosensitivity (49%), rash (45%), fatigue (40%), alopecia (36%) and cutaneous squamous cell carcinomas or keratoacanthomas (26%). In spite of the high incidence of new skin tumors, no mucosal squamous-cell carcinoma or metastases of cutaneous squamous cell carcinoma were observed and only four patients had to discontinue treatment because of toxicity [24] . In the pilot Phase II study specifically addressed to melanoma patients with brain metastases, which primary end-point was safety, vemurafenib was also generally well tolerated. The most frequent adverse events in the total of 24 patients included were arthralgia (38%), seizure (25%), alopecia (21%), diarrhoea (21%), dizziness (21%), muscular weakness (21%), maculopapular rash (21%), paresthesia [21%), solar dermatitis (21%)
future science group
Vemurafenib for the treatment of BRAF mutant metastatic melanoma and vomiting (21%) [27] . Patients enrolled in the randomized Phase III trial experienced a profile of side effects consistent with previous studies: keratoacanthomas or squamous cell carcinomas (20%), arthralgia (18%), rash (18%), fatigue (13%), photosensitivity skin reactions (12%), nausea (8%) and alopecia (8%) were the most reported toxicities. As in earlier clinical trials, all new skin tumors were successfully treated by simple excision [28] . In the updated survival analysis the most frequent grade 3–4 events observed in patients treated with vemurafenib were cutaneous squamous cell carcinomas (19%) and keratoacanthomas (10%), abnormal liver function tests (11%) and skin rash (9%) [15] . Vemurafenib toxicity in Phase I and II trials is summarized in Table 1. Results of an open-label, multicentric study that analyzed the safety of vemurafenib in 3226 patients with metastatic melanoma have recently been published. This representative of routine clinical practice study enrolled patients from 44 different countries over nearly 2 years. Patients with brain metastases, Eastern Cooperative Oncology Group Performance Status (ECO G PS) 2 and increased lactate dehydrogenase were allowed. The most common side effects found were skin rash (49%), arthralgia (39%), fatigue (34%), photosensitivity reaction (31%), alopecia (26%) and nausea (19%), which confirms the safety profile observed in the Phase I, II and III clinical trials. Grade 3 or 4 toxicities such as cutaneous squamous cell carcinomas (12%), skin rash (5%), liver function abnormalities (5%), arthralgia (3%) or fatigue (3%) were seen in 46% of patients. Patients aged 75 years or older reported higher incidence of grade 3 and grade 4 adverse events (59 and 4%, respectively) compared with younger patients (43 and 3%, respectively). A total of 14% of patients required dose reductions because of adverse events, the main reasons being arthralgia (3%) and skin rash (2%). Discontinuation rate attributed to adverse events was 6%, with QTc prolongation (
