2013年5月29日，美国食品药品监督管理局（FDA）批准了两种新药Dabrafenib（Tafinlar）和Trametinib（Mekinist）用于治疗转移性黑色素瘤 和不能行手术治疗的黑色素瘤病人，同时这两种新药的使用也可用于诊断该病人是否适合接受治疗。由于Dabrafenib和Trametinib刚刚获批，所以暂时还未获得相应的中文名称。
Dabrafenib和Trametinib为葛兰素史克（GlaxoSmithKline）公司研发的新药产品，均为口服片剂，但两种药物作用机制却稍有区别。
Dabrafenib为BRAF抑制剂，用于治疗瘤组织内BRAF V600E基因突变的黑色素瘤病人。Dabrafenib被认为是新一代的产品，和首个上市的BRAF抑制剂威罗菲尼（Zelboraf，罗氏公司）同属于一类药物。
Trametinib与Dabrafenib的作用机制有关联但稍有区别，它能够促进丝裂原活化，是一种细胞外信号调节激酶抑制剂（MEK抑制剂）。Trametinib是此类药物中首先被FDA批准的，用于治疗肿瘤组织内表达BRAF V600E/V600K突变基因的黑色素瘤病人。
在公布的新药获批通知中，FDA指出近半数起源于皮肤的黑色素瘤都存在BRAF基因突变。新药被批准的同时，FDA也批准了一项被称为THxID BRAF的基因检测项目，这项基因检测项目是与生物梅里埃公司共同研制的，可以检测出黑色素瘤病人BRAF基因是否存在V600E/V600K突变。
FDA坦言，黑色素瘤是皮肤疾病中导致死亡的最主要的病种。（美国）国家癌症研究所预计2013年有多达76,690名美国人被诊断为黑色素瘤，并且有9,480名死于此种疾病。
临床试验的数据
Dabrafenib的获批是基于一项名为BREAK 3研究的临床试验数据，该研究纳入了250名先前未经治疗的BRAF V600突变阳性的转移性黑色素瘤病人。研究结果显示在此类病人中，与达卡巴嗪的化疗相比，Dabrafenib显著改善了病人的中位无进展生存期（Dabrafenib，5.1个月 vs 达卡巴嗪, 2.7个月；P < 0.0001）。这些研究结果发表在：Lancet. 2012 Jul 28;380(9839):358-65.
FDA指出，接受Dabrafenib治疗的病人中出现的最严重的不良反应包括：发生皮肤鳞状细胞癌的风险升高，高烧伴发低血压、重度寒颤、脱水、肾功能衰竭，和需要糖尿病药物控制的高血糖水平。然而，在接受Dabrafenib治疗的病人中出现的最常见的不良反应包括：皮肤角化过度、头痛、高烧、关节痛、良性皮肤肿瘤的出现、脱发、手足综合症。
Trametinib研究（即METRIC临床试验研究）的关键部分与前一种药物稍有不同，其区别在于纳入的322例病人先前已经接受过化疗治疗。在METRIC研究中，与化疗相比，Trametinib显著改善了病人的无进展生存期和总生存期。该项研究的结果发表在：New England Journal of Medicine（N Engl J Med. 2012 Jul 12;367(2):107-14. ）。
FDA指出，接受Trametinib治疗的病人中出现的最严重的不良反应包括：心脏衰竭、肺炎、皮肤感染、失明。最常见的不良反应包括：皮疹、腹泻、组织肿胀（外周性水肿）、粉刺样皮肤发疹。
FDA也指出，育龄期妇女使用Dabrafenib和Trametinib有导致胎儿损害的风险，男性病人和女性病人使用该两种药物有导致不孕不育的风险。
联合应用还在研究中
FDA强调，Dabrafenib和Trametinib获批时是单独应用治疗黑色素瘤的，并没有将其联合应用。然而，许多医生将这两种药物联合应用了起来，实际上药品生产厂商也正在进行这两种药物联合应用治疗黑色素瘤的临床试验。
Dabrafenib和Trametinib联合应用的临床试验的初步结果表明，与威罗菲尼单独使用相比，两药联合使用毒性减小，特别是能够减少次生皮肤癌的发生。
目前，葛兰素史克公司正在进行名为COMBI-AD的三期临床试验，该研究将Dabrafenib与Trametinib联合应用治疗BRAF V600突变的黑色素瘤病人，这些病人的肿瘤组织已被手术完全切除。然而，该公司指出，此类病人复发的风险颇高，Dabrafenib与Trametinib的联合应用可以用来测定肿瘤复发是否会延迟或是否可以预防复发的发生。

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.