2013年5月29日，美国食品和药物管理局批准了两个新的药物：Tafinlar（dabrafenib）和Mekinist（trametinib），用于晚期（转移性）或无法切除的黑色素瘤治疗。
黑色素瘤是最危险的皮肤癌，已成为皮肤疾病死亡的首要原因。美国国家癌症研究所估计，2013年将有76690名美国人被诊断患有黑色素瘤，9480人将死于此种疾病。
Tafinlar是BRAF抑制剂，被批准用于肿瘤表达BRAFV600E基因突变的黑色素瘤患者的治疗。Mekinist是MEK抑制剂，被批准用于肿瘤表达BRAFV600E或V600K基因突变的黑色素瘤患者的治疗。皮肤黑色素瘤约一半有BRAF基因突变。Tafinlar和Mekinist获准作为单独用药，而不是组合治疗。
FDA批准Tafinlar和Mekinist的BRAF基因诊断试剂为THxID，该伴随诊断试剂将有助于确定患者黑色素瘤细胞BRAF基因有V600E或V600K突变。
FDA的药物评价和研究中心、血液学和肿瘤学产品办公室主任、医学博士RichardPazdur说：“开发Tafinlar和Mekinist是基于我们对疾病生物学途径理解的提升，它们已经是过去两年中FDA批准的第三和第四个治疗转移性黑色素瘤药物。”
Zelboraf（vemurafenib）和Yervoy（ipilimumab）在2011年获准用于转移性或无法切除黑色素瘤的治疗。
“共同批准Tafinlar和Mekinist和BRAF基因突变检测诊断的第二个伴侣了承担的医药和诊断合作伙伴开发的产品检测和针对癌症的分子司机阿尔贝托·古铁雷斯说：”博士，主任在FDA的器械和辐射健康中心体外诊断器械和辐射健康办公室。
FDA批准ThxID作为BRAF检测是基于支持Tafinlar和Mekinist的临床研究数据。收集患者黑色素瘤组织样品测试BRAF突变。
Tafinlar在250例BRAFV600E基因突变阳性、转移性或无法切除黑色素瘤患者中开展临床研究。患者被随机分配接受Tafinlar或化疗药物达卡巴嗪。接受Tafinlar治疗患者比接受达卡巴嗪的患者肿瘤生长延期2.4个月。
接受Tafinlar治疗报告的最严重不良反应包括：皮肤癌（皮肤鳞状细胞癌）风险增加、低血压引发的不明原因发热、严重寒颤、脱水、肾功能衰竭和血糖水平增高需要改变糖尿病治疗药物或需要开始使用控制糖尿病药物。
接受Tafinlar治疗患者报告的最常见不良反应包括：皮肤增厚、角化、头痛、发热、关节疼痛、非癌症皮肤瘤、脱发和手足综合征。
Mekinist在322例转移性或无法切除、BRAFV600E或V600K基因突变的黑色素瘤患者中进行了临床研究。患者被随机分配接受Mekinist或化疗治疗。接受Mekinist治疗比接受化疗的患者肿瘤生长延迟3.3个月。以前曾使用BRAF抑制剂或Tafinlar的其他患者并没有从Mekinist获益。
接受Mekinist治疗患者报告的最严重不良反应包括：心脏衰竭、肺部炎症、皮肤感染和视力丧失。常见不良反应包括：皮疹、腹泻、组织肿胀（外周性水肿）和类似粉刺的皮疹。
应告知育龄妇女Tafinlar和Mekinist可能会对胎儿造成伤害。也应告知男性和女性Tafinlar和Mekinist可能引至不孕。
Tafinlar和Mekinist由总部设在三角研究园的葛兰素史克公司生产，NCTHxIDBRAF套盒由法国格勒诺布尔的生物梅里埃（bioMérieux）生产。Yervoy由纽约市的施贵宝公司销售，Zelboraf由总部位于旧金山的罗氏集团成员基因泰克公司销售。
另据路透社讯，葛兰素史克公司将开始生产Tafinlar和Mekinist，最迟第三季度初患者就可获得Tafinlar和Mekinist的处方。

Two new GSK oral oncology treatments, BRAF-inhibitor Tafinlar® (dabrafenib) capsules and the first MEK-inhibitor Mekinist™ (trametinib) tablets, approved by FDA as single-agent therapies
Issued: Wednesday 29 May 2013, London, UK and Philadelphia, U.S.
- Both approved for unresectable or metastatic melanoma with BRAF V600E mutation; Mekinist also approved for BRAF V600K mutation
GlaxoSmithKline plc [LSE/NYSE: GSK] announced today that the U.S. Food and Drug Administration (FDA) has approved both TAFINLAR® (dabrafenib) and MEKINIST™ (trametinib). Tafinlar is indicated as a single-agent oral treatment for unresectable melanoma (melanoma that cannot be removed by surgery) or metastatic melanoma (melanoma which has spread to other parts of the body) in adult patients with BRAF V600E mutation. Tafinlar is not indicated for the treatment of patients with wild-type BRAF melanoma. Mekinist is indicated as a single-agent oral treatment for unresectable or metastatic melanoma in adult patients with BRAF V600E or V600K mutations. Mekinist is not indicated for the treatment of patients who have received a prior BRAF inhibitor therapy. These mutations must be detected by an FDA-approved test, such as the companion diagnostic assay from bioMérieux S.A., THxID™-BRAF.
“With today’s FDA approvals, GSK can now offer two new single-agent therapies to selected patients who have metastatic melanoma, a devastating disease with very low survival rates and few treatment options,” said Paolo Paoletti, M.D., President, GlaxoSmithKline Oncology. “GSK Oncology has been focused on progressing research in the most efficient manner possible, and we’re pleased to bring Tafinlar and Mekinist to physicians and their patients in rapid development times.”
Among those with metastatic melanoma, approximately half have a BRAF mutation, which is an abnormal change in a gene that can enable some melanoma tumours to grow and spread. [1]
Tafinlar and Mekinist are each approved for patients with the BRAF V600E mutation, which accounts for approximately 85 percent of all BRAF V600 mutations in metastatic melanoma. [2] Mekinist is also approved for patients with the V600K mutation, which makes up approximately 10 percent of all BRAF V600 mutations in metastatic melanoma.2
“MEK has been pursued as a therapeutic target in cancer for more than a decade,” said Keith Flaherty, M.D., Director of Developmental Therapeutics, Massachusetts General Hospital Cancer Center, and principal investigator of the Phase III METRIC trial. “Based on the clear improvement versus chemotherapy in progression-free survival, trametinib represents the first validated MEK inhibitor. We welcome it as a new treatment option for patients with this disease.”
As part of the FDA approval, which was based on clinical studies evaluating the efficacy and safety of these products, warnings and precautions were also identified. Dabrafenib can cause serious side effects, some of which can be life threatening, including increasing the risk of developing new primary cutaneous malignancies (new skin cancers), tumour promotion in BRAF wild-type melanoma, serious febrile drug reactions (severe fevers), hyperglycaemia (blood sugar problems), uveitis and iritis (severe eye problems), haemolytic anaemia in patients with glucose-6-phosphate dehydrogenase (G6PD) deficiency and embryofoetal toxicity (potential harm to the unborn baby in pregnant women). Trametinib can cause serious side effects, some of which can be life threatening, including cardiomyopathy (heart problems, including heart failure), retinal pigment epithelial detachment (RPED) and retinal vein occlusion (RVO) (eye problems including blindness), interstitial lung diseaseor pneumonitis (lung or breathing problems), serious skin toxicity (rash) and embryofoetal toxicity.  
GSK will be making Tafinlar and Mekinist available for prescription no later than in the early third quarter of 2013.
In 2010, GSK entered a collaboration with bioMérieux to develop a companion diagnostic test to detect BRAF V600 (V600E and V600K) gene mutations found in several cancers, including melanoma. bioMérieux has received FDA pre-market approval of THxID™-BRAF. Currently, it is the only FDA-approved test that detects the V600K mutation.
Tafinlar (dabrafenib) Clinical Data
The approval of dabrafenib is based on results from one multicenter, international trial, specifically the pivotal, open-label Phase III BREAK-3 study that randomised 250 previously untreated adult patients with BRAF V600E mutation-positive unresectable or metastatic melanoma to receive dabrafenib or dacarbazine (chemotherapy) in a 3:1 ratio, respectively. The primary endpoint was progression-free survival (PFS) as assessed by the investigator. Other pre-specified endpoints included independent radiology review committee (IRRC) assessed PFS, confirmed objective response rate (ORR) and duration of response. Twenty-eight patients (44%) crossed over from the dacarbazine arm at the time of disease progression to receive dabrafenib.
The study demonstrated a statistically significant increase in PFS in patients treated with dabrafenib, compared to dacarbazine (HR=0.33; [95% CI: 0.20, 0.54], p<0.0001). The median PFS was 5.1 months with dabrafenib (95% CI: 4.9, 6.9) compared to 2.7 months with dacarbazine (95% CI: 1.5, 3.2). The ORR with dabrafenib was 52 percent (95% CI: 44, 59) versus 17 percent with dacarbazine (95% CI: 9, 29).
In this study, the most common adverse reactions (greater than or equal to 10%) of any grade for dabrafenib included hyperkeratosis (thickening of the outer layer of the skin) (37%), headache (32%), pyrexia (fever) (28%), arthralgia (joint aches) (27%), papilloma (warts) (27%), alopecia (hair loss) (22%), palmar-plantar erythrodysesthesia (redness, swelling, peeling or tenderness of hands or feet) (20%), rash (17%), back pain (12%), cough (12%), myalgia (muscle aches) (11%), constipation (11%) and nasopharyngitis (cold-like symptoms) (10%).
Dabrafenibwas also prospectively evaluated in adult patients with BRAF V600E mutation-positive melanoma, metastatic to the brain. The single-arm, open-label Phase II trial enrolled patients into two cohorts. Patients in Cohort A (n=74) had received no prior local therapy for brain metastases, while patients in Cohort B (n=65) had received at least one local therapy for brain metastases, including but not limited to surgical resection, whole brain radiotherapy or stereotactic radiosurgery such as gamma knife, linear-accelerated-based radiosurgery, charged particles or CyberKnife. In addition, patients in Cohort B were required to have evidence of disease progression in a previously treated lesion or an untreated lesion. Additional eligibility criteria were at least one measurable lesion of 0.5 cm or greater in largest diameter on contrast-enhanced MRI, stable or decreasing corticosteroid dose, and no more than two prior systemic regimens for treatment of metastatic disease.
The primary outcome measure was the estimation of the overall intracranial response rate (OIRR) in each cohort. The OIRR for Cohort A was 18 percent (95% CI: 9.7, 28.2). For Cohort B, the OIRR was also 18 percent (95% CI: 9.9, 30.0). The median duration of response was 4.6 months (95% CI: 2.8, Not Reached) and 4.6 months (95% CI: 1.9, 4.6) in Cohort A and Cohort B, respectively.
Mekinist (trametinib) Clinical Data
The approval of trametinib is based on results from the open-label, international Phase III METRIC study.  In this study, 322 unresectable or metastatic melanoma adult patients with a BRAF V600E or V600K mutation, who had no more than one prior chemotherapy regimen for advanced or metastatic disease and no prior BRAF or MEK inhibitor treatment, were randomised to receive trametinib or chemotherapy in a 2:1 ratio, respectively.
The study demonstrated a statistically significant increase in PFS in patients treated with trametinib, compared to chemotherapy (HR= 0.47; [95% CI: 0.34, 0.65], p<0.0001). The median PFS was 4.8 months for patients taking trametinib (95% CI: 4.3, 4.9) compared to 1.5 months for chemotherapy (95% CI: 1.4, 2.7). Fifty-one patients (47%) crossed over from the chemotherapy arm at the time of disease progression to receive trametinib.
The most common adverse reactions (greater than or equal to 10%) of any grade in patients receiving trametinib included rash (57%), diarrhoea (43%), lymphoedema (swelling of the face, arms or legs) (32%), dermatitis acneiform (acne-like rash) (19%), stomatitis (mouth sores) (15%), hypertension (new or worsening high blood pressure) (15%), abdominal pain (13%), haemorrhage (bleeding) (13%), dry skin (11%), pruritis (itching) (10%) and paronychia (nail infection) (10%).
About Melanoma and Metastatic Melanoma
Melanoma is the most serious and deadly form of skin cancer. [3] According to statistics from the National Cancer Institute, in 2013 there will be an estimated 9,480 deaths resulting from melanoma in the United States. [4] When melanoma spreads in the body, the disease is called metastatic melanoma. [5]Approximately half of all people with metastatic melanoma have a BRAF mutation, which is an abnormal change in a gene that can enable some melanoma tumours to grow and spread.2 One in two patients worldwide with metastatic melanoma is expected to survive for a year after diagnosis, [6] while in the U.S., the five-year survival rate was 16 percent (2003-2009). [7] The median age of a newly diagnosed metastatic melanoma patient is almost a decade younger than other cancers. [8]
About Tafinlar® (dabrafenib)
Tafinlar (dabrafenib) is now approved for the treatment of adult patients with unresectable or metastatic melanoma with BRAF V600E mutation as detected by an FDA-approved test. Limitation of use: Tafinlar is not recommended for use in patients with wild-type BRAF melanoma.
Tafinlar is not approved or licensed in Europe and may not be approved in other parts of the world for the treatment of patients with BRAF V600 mutation-positive unresectable melanoma or metastatic melanoma.
Full U.S. Prescribing Information and Medication Guide will be available soon at us.gsk.com. Prior to the label being posted online, a copy of the label may be requested from one of the GSK Media or Investor Relations contacts listed in the “GlaxoSmithKline Inquiries” section at the end of this document.
About MekinistTM (trametinib)
Mekinist(trametinib) is now approved for the treatment of adult patients with unresectable or metastatic melanoma with BRAF V600E and V600K mutations as detected by an FDA-approved test. Limitation of use: Mekinist is not indicated for the treatment of patients who have received a prior BRAF inhibitor therapy.
Mekinist was in-licensed by GSK in 2006. GSK holds the worldwide exclusive rights to develop, manufacture and commercialise Mekinist, while Japan Tobacco retains co-promotion rights in Japan.
Mekinist is not approved or licensed in Europe and may not be approved in other parts of the world for the treatment of patients with BRAF V600 mutation-positive unresectable melanoma or metastatic melanoma.
Full U.S. Prescribing Information and Medication Guide will be available soon at us.gsk.com. Prior to the label being posted online, a copy of the label may be requested from one of the GSK Media or Investor Relations contacts listed in the “GlaxoSmithKline Inquiries” section at the end of this document.
IMPORTANT SAFETY INFORMATION FOR TAFINLAR® (dabrafenib)
WARNINGS AND PRECAUTIONS
New Primary Cutaneous Malignancies
TAFINLAR® (dabrafenib) results in an increased incidence of cutaneous squamous cell carcinoma, keratoacanthoma and melanoma. In the pivotal trial of dabrafenib, cuSCC occurred in 7% (14/147) of patients treated with dabrafenib and in none of the patients treated with dacarbazine. Across clinical trials of dabrafenib (n=586), the incidence of cuSCC was 11%. The median time to first cuSCC was 9 weeks (range: 1 to 53 weeks). Of those, patients who developed a cuSCC, approximately 33% developed one or more cuSCC with continued dabrafenib. The median time between diagnosis of the first cuSCC and the second cuSCC was 6 weeks.
In the pivotal trial of dabrafenib, the incidence of new primary malignant melanomas was 2% (3/187) for patients receiving dabrafenib while no chemotherapy-treated patient was diagnosed with new primary malignant melanoma.
Tumour Promotion in BRAF Wild-Type Melanoma
In vitroexperiments have demonstrated paradoxical activation of MAP-kinase signaling and increased cell proliferation in BRAF wild-type cells which are exposed to BRAF inhibitors.
Serious Febrile Drug Reactions
In the pivotal trial of Tafinlar (dabrafenib), serious febrile drug reactions, defined as serious cases of fever or fever of any severity accompanied by hypotension, rigors or chills, dehydration, or renal failure in the absence of another identifiable cause (e.g., infection) occurred in 3.7% (7/187) of patients treated with dabrafenib and in none of the patients treated with dacarbazine. The incidence of fever (serious and non-serious) was 28% in patients treated with dabrafenib and 10% in patients treated with dacarbazine. In patients treated with dabrafenib, the median time to initial onset of fever (any severity) was 11 days (range: 1 to 202 days), and the median duration of fever was 3 days (range 1 to 129 days).
Hyperglycaemia
Hyperglycaemia requiring an increase in the dose of, or initiation of insulin or oral hypoglycaemic agent therapy, can occur with Tafinlar (dabrafenib). In the pivotal trial of dabrafenib, 5 of 12 patients with a history of diabetes required more intensive hypoglycaemic therapy while taking dabrafenib. The incidence of Grade 3 hyperglycaemia based on laboratory values was 6% (12/187) in patients treated with dabrafenib compared to none of the dacarbazine-treated patients.
Uveitis and Iritis
Uveitis (including iritis) occurred in 1% (6/586) of patients treated with Tafinlar (dabrafenib) across clinical trials.
Glucose-6-Phosphate Dehydrogenase Deficiency
Tafinlar (dabrafenib), which contains a sulfonamide moiety, confers a potential risk of haemolytic anaemia in patients with glucose-6-phosphate dehydrogenase deficiency.
Embryofoetal Toxicity
Based on its mechanism of action, Tafinlar (dabrafenib) can cause foetal harm when administered to a pregnant woman. Dabrafenib was teratogenic and embryotoxic in rats at doses three times greater than the human exposure at the recommended clinical dose.
Most Common Adverse Reactions
The most common adverse reactions (greater than or equal to 10%) of any grade included hyperkeratosis (37%), headache (32%), pyrexia (28%), arthralgia (27%), papilloma (27%), alopecia (22%), palmar-plantar erythrodysesthesia (20%), rash (17%), back pain (12%), cough (12%), constipation (11%), myalgia (11%), and nasopharyngitis (10%).
The most common serious adverse reactions (greater than or equal to 2%) of grades 3 and 4 include cuSCC (4%), back pain (3%), pyrexia (3%), constipation (2%), and palmar-plantar erythrodysesthesia (2%).
Drug Interactions
Effects of Other Drugs on Dabrafenib
Drugs that Inhibit or Induce Drug-Metabolising Enzymes: Dabrafenib is primarily metabolised by CYP2C8 and CYP3A4. Strong inhibitors or inducers of CYP3A4 or CYP2C8 may increase or decrease, respectively, concentrations of dabrafenib.

Drugs that Affect Gastric pH: Drugs that alter the pH of the upper GI tract (e.g., proton pump inhibitors, H2-receptor antagonists, antacids) may alter the solubility of dabrafenib and reduce its bioavailability. However, no formal clinical trial has been conducted to evaluate the effect of gastric pH-altering agents on the systemic exposure of dabrafenib.
Effects of Dabrafenib on Other Drugs
Dabrafenib induces CYP3A4 and may induce other enyzmes including CYP2B6, CYP2C8, CYP2C9, CYP2C19, and UDP glucuronosyltransferases (UGT) and may induce transporters. Dabrafenib decreased the maximum concentration (Cmax) and area under the curve (AUC) of midazolam (a substrate of CYP3A4) by 61% and 74%, respectively. Coadministration of Tafinlar with other substrates of these enzymes, including warfarin, dexamethasone, or hormonal contraceptives, can result in decreased concentrations and loss of efficacy.
Females and Males of Reproductive Potential
Tafinlar (dabrafenib) may impair fertility in males.
Important Safety Information for Mekinist™ (trametinib)
WARNINGS AND PRECAUTIONS
Cardiomyopathy
In the pivotal trial of MEKINIST™(trametinib), cardiomyopathy [defined as cardiac failure, left ventricular dysfunction, or decreased left ventricular ejection fraction (LVEF)] occurred in 7% (14/211) of patients treated with trametinib; no chemotherapy-treated patient developed cardiomyopathy. The median time to onset of cardiomyopathy in patients treated with trametinib was 63 days (range 16 to 156 days); cardiomyopathy was identified within the first month of treatment with trametinib in five of these 14 patients. Four percent of patients in the pivotal trial of trametinib required discontinuation (4/211) and/or dose reduction (7/211) of trametinib. Cardiomyopathy resolved in 10 of these 14 (71%) patients.
Across clinical trials of trametinib at the recommended dose (n=329), 11% of patients developed evidence of cardiomyopathy (decrease in LVEF below institutional lower limits of normal with an absolute decrease in LVEF greater than or equal to 10% below baseline), and 5% demonstrated a decrease in LVEF below institutional lower limits of normal with an absolute decrease in LVEF of greater than or equal to 20% below baseline.
Retinal Pigment Epithelial Detachments
Retinal pigment epithelial detachments (RPED) can occur during treatment with Mekinist (trametinib).
In the pivotal trial of trametinib, where ophthalmologic examinations including retinal evaluation were performed pretreatment and at regular intervals during treatment, one patient (0.5%) receiving trametinib developed RPED and no cases of RPED were identified in chemotherapy-treated patients.
Across all clinical trials of trametinib, the incidence of RPED was 0.8% (14/1749).
Retinal detachments were often bilateral and multifocal, occurring in the macular region of the retina. RPED led to reduction in visual acuity that resolved after a median of 11.5 days (range 3 to 71 days) following the interruption of dosing with trametinib, although Ocular Coherence Tomography (OCT) abnormalities persisted beyond a month in at least several cases.
Retinal Vein Occlusion (RVO)
Across all clinical trials of Mekinist (trametinib), the incidence of RVO was 0.2% (4/1749). An RVO may lead to macular edema, decreased visual function, neovascularization, and glaucoma.
Interstitial Lung Disease (ILD)
In clinical trials of Mekinist (trametinib) at the recommended dose (n=329), interstitial lung disease (ILD) or pneumonitis occurred in 1.8% of patients.
In the pivotal trial of trametinib, 2.4% (5/211) of patients treated with trametinib developed ILD or pneumonitis; all five patients required hospitalization.
The median time to first presentation of ILD or pneumonitis was 160 days (range 60 to 172 days).
Serious Skin Toxicity
In the pivotal trial of Mekinist (trametinib), the overall incidence of skin toxicity including rash, dermatitis, acneiform rash, palmar-plantar erythrodysesthesia syndrome, and erythema was 87% in patients treated with trametinib and 13% in chemotherapy-treated patients. Severe skin toxicity occurred in 12% of patients treated with trametinib.
Skin toxicity requiring hospitalization occurred in 6% of patients treated with trametinib, most commonly for secondary infections of the skin requiring intravenous antibiotics or severe skin toxicity without secondary infection. In comparison, no patients treated with chemotherapy required hospitalization for severe skin toxicity or infections of the skin.
The median time to onset of skin toxicity in patients treated with trametinib was 15 days (range 1 to 221 days) and median time to resolution of skin toxicity was 48 days (range 1 to 282 days).
Reductions in the dose of trametinib were required in 12%, and permanent discontinuation of trametinib was required in 1% of patients with skin toxicity. 
Embryofoetal Toxicity
Based on its mechanism of action, Mekinist (trametinib) can cause foetal harm when administered to a pregnant woman. Trametinib was embryotoxic and abortifacient in rabbits at doses greater than or equal to those resulting in exposures approximately 0.3 times the human exposure at the recommended clinical dose.
Adverse Reactions
In the pivotal trial of Mekinist (trametinib), the most common adverse reactions (greater than or equal to 10%) of any grade were rash (57%), diarrhoea (43%), lymphoedema (32%), dermatitis acneiform (19%), stomatitis (15%), hypertension (15%), abdominal pain (13%), haemorrhage (13%), dry skin (11%), pruritis (10%) and paronychia (10%).
In the pivotal trial of trametinib, the most common serious adverse reactions (≥2%) grades 3 and 4 were hypertension (12%), rash (8%), pruritis (2%), and stomatitis (2%). 
Females and Males of Reproductive Potential
Mekinist (trametinib) may impair fertility in females.