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2011年8月，新型抗癌Zelboraf(vemurafenib)口服片获美国（FDA）批准用于治疗后期(转移)或不可切除黑色素瘤，最危险的皮肤癌类型患者。
ZELBORAF® is a kinase inhibitor indicated for the treatment of patients with unresectable or metastatic melanoma with BRAF V600E mutation as detected by an FDA-approved test. (1, 2.1) Limitation of Use: ZELBORAF is not indicated for treatment of patients with wild-type BRAF melanoma. (2.1, 5.2) DOSAGE AND ADMINISTRATION Confirm the presence of BRAF V600E mutation in tumor specimens prior to initiation of treatment with ZELBORAF. (2.1) Recommended dose: 960 mg orally twice daily taken approximately 12 hours apart with or without a meal. (2.2) DOSAGE FORMS AND STRENGTHS Tablet: 240 mg (3) CONTRAINDICATIONS None (4) WARNINGS AND PRECAUTIONS New Primary Cutaneous Malignancies: Perform dermatologic evaluations prior to initiation of therapy, every 2 months while on therapy, and for up to 6 months following discontinuation of ZELBORAF. Manage with excision and continue treatment without dose adjustment. (5.1) New Non-Cutaneous Squamous Cell Carcinoma: Evaluate for symptoms or clinical signs of new non-cutaneous SCC before initiation of treatment and periodically during treatment. (5.1) Other Malignancies: Monitor patients receiving ZELBORAF closely for signs or symptoms of other malignancies (5.1). Tumor Promotion in BRAF Wild-Type Melanoma: Increased cell proliferation can occur with BRAF inhibitors (5.2). Serious Hypersensitivity Reactions including anaphylaxis and Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS Syndrome): Discontinue ZELBORAF for severe hypersensitivity reactions. (5.3) Severe Dermatologic Reactions, including Stevens-Johnson Syndrome and Toxic Epidermal Necrolysis: Discontinue ZELBORAF for severe dermatologic reactions. (5.4) QT Prolongation: Monitor ECG and electrolytes before and during treatment. Withhold ZELBORAF for QTc of 500 ms or greater. Correct electrolyte abnormalities and control for cardiac risk factors for QT prolongation. (5.5) Hepatotoxicity: Measure liver enzymes and bilirubin before initiating ZELBORAF and monitor monthly during treatment. (5.6) Photosensitivity: Advise patients to avoid sun exposure. (5.7) Serious Ophthalmologic Reactions: Monitor for signs and symptoms of uveitis. (5.8) Embryo-Fetal Toxicity: Can cause fetal harm. Advise females of the potential risk to the fetus and to use effective contraception. (5.9, 8.1, 8.3) Radiation Sensitization and Radiation Recall: Severe cases have been reported. (5.10). Renal Failure: Measure serum creatinine before initiating ZELBORAF and monitor periodically during treatment (5.11). ADVERSE REACTIONS Most common adverse reactions (≥ 30%) are arthralgia, rash, alopecia, fatigue, photosensitivity reaction, nausea, pruritus, and skin papilloma. (6.1) To report SUSPECTED ADVERSE REACTIONS, contact Genentech at 1-888-835-2555 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. DRUG INTERACTIONS Avoid concomitant administration of ZELBORAF with strong CYP3A4 inhibitors or inducers. (7.1) CYP1A2 Substrates: ZELBORAF can increase concentrations of CYP1A2 substrates. Avoid concomitant use of ZELBORAF with CYP1A2 substrates with a narrow therapeutic window. If coadministration cannot be avoided, monitor closely for toxicities and consider dose reduction of CYP1A2 substrates. (7.2). USE IN SPECIFIC POPULATIONS Lactation: Do not breastfeed while taking Zelboraf. (8.2) See 17 for PATIENT COUNSELING INFORMATION and Medication Guide. Revised: 8/2016 FULL PRESCRIBING INFORMATION: CONTENTS* 1 INDICATIONS AND USAGE ZELBORAF® is indicated for the treatment of patients with unresectable or metastatic melanoma with BRAF V600E mutation as detected by an FDA-approved test. Limitation of Use: ZELBORAF is not indicated for treatment of patients with wild-type BRAF melanoma [see Warnings and Precautions (5.2)]. 2 DOSAGE AND ADMINISTRATION 2.1 Patient Selection Confirm the presence of BRAF V600E mutation in tumor specimens prior to initiation of treatment with ZELBORAF [see Warnings and Precautions (5.2)]. Information on FDA-approved tests for the detection of BRAF V600 mutations in melanoma is available at http://www.fda.gov/CompanionDiagnostics. 2.2 Recommended Dose The recommended dose of ZELBORAF is 960 mg (four 240 mg tablets) orally every 12 hours with or without a meal. A missed dose can be taken up to 4 hours prior to the next dose. Treat patients with ZELBORAF until disease progression or unacceptable toxicity occurs. Do not take an additional dose if vomiting occurs after ZELBORAF administration, but continue with the next scheduled dose. Do not crush or chew the tablets. 2.3 Dose Modifications For New Primary Cutaneous Malignancies: No dose modifications are recommended. For Other Adverse Reactions: Permanently discontinue ZELBORAF for any of the following: Grade 4 adverse reaction, first appearance (if clinically appropriate) or second appearance QTc prolongation > 500 ms and increased by > 60 ms from pre-treatment values [see Warnings and Precautions (5.5)] Withhold ZELBORAF for NCI-CTCAE (v4.0) intolerable Grade 2 or greater adverse reactions. Upon recovery to Grade 0–1, restart ZELBORAF at a reduced dose as follows: 720 mg twice daily for first appearance of intolerable Grade 2 or Grade 3 adverse reactions 480 mg twice daily for second appearance of Grade 2 (if intolerable) or Grade 3 adverse reactions or for first appearance of Grade 4 adverse reaction (if clinically appropriate) Do not dose reduce to below 480 mg twice daily. 3 DOSAGE FORMS AND STRENGTHS Tablet: 240 mg. 4 CONTRAINDICATIONS None. 5 WARNINGS AND PRECAUTIONS 5.1 New Primary Malignancies Cutaneous Malignancies Cutaneous squamous cell carcinoma, keratoacanthoma, and melanoma occurred at a higher incidence in patients receiving ZELBORAF compared to those in the control arm in Trial 1. The incidence of cutaneous squamous cell carcinomas (cuSCC) and keratoacanthomas in the ZELBORAF arm was 24% compared to < 1% in the dacarbazine arm [see Adverse Reactions (6.1)]. The median time to the first appearance of cuSCC was 7 to 8 weeks; approximately 33% of patients who developed a cuSCC while receiving ZELBORAF experienced at least one additional occurrence with median time between occurrences of 6 weeks. Potential risk factors associated with cuSCC observed in clinical studies using ZELBORAF included age (≥ 65 years), prior skin cancer, and chronic sun exposure. In Trial 1, new primary malignant melanoma occurred in 2.1% (7/336) of patients receiving ZELBORAF compared to none of the patients receiving dacarbazine. Perform dermatologic evaluations prior to initiation of therapy and every 2 months while on therapy. Manage suspicious skin lesions with excision and dermatopathologic evaluation. Consider dermatologic monitoring for 6 months following discontinuation of ZELBORAF. Non-Cutaneous Squamous Cell Carcinoma Non-cutaneous squamous cell carcinomas (non-cuSCC) of the head and neck can occur in patients receiving ZELBORAF [see Adverse Reactions (6.1)]. Monitor patients receiving ZELBORAF closely for signs or symptoms of new non-cuSCC. Other Malignancies Based on mechanism of action, ZELBORAF may promote malignancies associated with activation of RAS through mutation or other mechanisms [see Warnings and Precautions (5.2)]. Monitor patients receiving ZELBORAF closely for signs or symptoms of other malignancies. 5.2 Tumor Promotion in BRAF Wild-Type Melanoma In vitro experiments have demonstrated paradoxical activation of MAP-kinase signaling and increased cell proliferation in BRAF wild-type cells that are exposed to BRAF inhibitors. Confirm evidence of BRAF V600E mutation in tumor specimens prior to initiation of ZELBORAF [see Indications and Usage (1) and Dosage and Administration (2.1)]. 5.3 Hypersensitivity Reactions Anaphylaxis and other serious hypersensitivity reactions can occur during treatment and upon re-initiation of treatment with ZELBORAF. Severe hypersensitivity reactions included generalized rash and erythema, hypotension, and drug reaction with eosinophilia and systemic symptoms (DRESS syndrome). Permanently discontinue ZELBORAF in patients who experience a severe hypersensitivity reaction [see Adverse Reactions (6.2)]. 5.4 Dermatologic Reactions Severe dermatologic reactions, including Stevens-Johnson syndrome and toxic epidermal necrolysis, can occur in patients receiving ZELBORAF. Permanently discontinue ZELBORAF in patients who experience a severe dermatologic reaction [see Adverse Reactions (6.1)]. 5.5 QT Prolongation Concentration-dependent QT prolongation occurred in an uncontrolled, open-label QT sub-study in previously treated patients with BRAF V600E mutation-positive metastatic melanoma [see Clinical Pharmacology (12.2)]. QT prolongation may lead to an increased risk of ventricular arrhythmias, including Torsade de Pointes. Do not start treatment in patients with uncorrectable electrolyte abnormalities, QTc > 500 ms, or long QT syndrome, or in patients who are taking medicinal products known to prolong the QT interval. Prior to and following treatment initiation or after dose modification of ZELBORAF for QTc prolongation, evaluate ECG and electrolytes (including potassium, magnesium, and calcium) after 15 days, monthly during the first 3 months, and then every 3 months thereafter or more often as clinically indicated. Withhold ZELBORAF in patients who develop QTc > 500 ms (Grade 3). Upon recovery to QTc ≤ 500 ms (Grade ≤ 2), restart at a reduced dose. Permanently discontinue ZELBORAF treatment if the QTc interval remains > 500 ms and increased > 60 ms from pre-treatment values after controlling cardiac risk factors for QT prolongation (e.g., electrolyte abnormalities, congestive heart failure, and bradyarrhythmias) [see Dosage and Administration (2.3)]. 5.6 Hepatotoxicity Liver injury leading to functional hepatic impairment, including coagulopathy or other organ dysfunction, can occur with ZELBORAF [see Adverse Reactions (6.1)]. Monitor transaminases, alkaline phosphatase, and bilirubin before initiation of treatment and monthly during treatment, or as clinically indicated. Manage laboratory abnormalities with dose reduction, treatment interruption, or treatment discontinuation [see Dosage and Administration (2.3)]. Concurrent Administration with Ipilimumab The safety and effectiveness of ZELBORAF in combination with ipilimumab have not been established [see Indications and Usage (1)]. In a dose-finding trial, Grade 3 increases in transaminases and bilirubin occurred in a majority of patients who received concurrent ipilimumab (3 mg/kg) and vemurafenib (960 mg BID or 720 mg BID) [see Drug Interactions (7.3)]. 5.7 Photosensitivity Mild to severe photosensitivity can occur in patients treated with ZELBORAF [see Adverse Reactions (6.1)]. Advise patients to avoid sun exposure, wear protective clothing and use a broad spectrum UVA/UVB sunscreen and lip balm (SPF ≥ 30) when outdoors. Institute dose modifications for intolerable Grade 2 or greater photosensitivity [see Dosage and Administration (2.2)]. 5.8 Ophthalmologic Reactions Uveitis, blurry vision, and photophobia can occur in patients treated with ZELBORAF. In Trial 1, uveitis, including iritis, occurred in 2.1% (7/336) of patients receiving ZELBORAF compared to no patients in the dacarbazine arm. Treatment with steroid and mydriatic ophthalmic drops may be required to manage uveitis. Monitor patients for signs and symptoms of uveitis. 5.9 Embryo-Fetal Toxicity Based on its mechanism of action, ZELBORAF can cause fetal harm when administered to a pregnant woman. Advise pregnant women of the potential risk to a fetus. Advise females of reproductive potential to use effective contraception during treatment with ZELBORAF and for 2 weeks after the final dose [see Use in Specific Populations (8.1, 8.3) and Clinical Pharmacology (12.1)]. 5.10 Radiation Sensitization and Radiation Recall Radiation sensitization and recall, in some cases severe, involving cutaneous and visceral organs have been reported in patients treated with radiation prior to, during, or subsequent to vemurafenib treatment. Fatal cases have been reported in patients with visceral organ involvement. [see Adverse Reactions (6.2)]. Monitor patients closely when vemurafenib is administered concomitantly or sequentially with radiation treatment. 5.11 Renal Failure Renal failure, including acute interstitial nephritis and acute tubular necrosis, can occur with ZELBORAF. Twenty-six percent of ZELBORAF-treated patients and 5% of dacarbazine-treated patients experienced Grade 1-2 creatinine elevations [greater than 1 and up to 3 times upper limit of normal (ULN)]; 1.2% of ZELBORAF-treated patients and 1.1% of dacarbazine-treated patients experienced Grade 3-4 creatinine elevations (greater than 3 times ULN). Measure serum creatinine before initiation of ZELBORAF and periodically during treatment. 6 ADVERSE REACTIONS The following adverse reactions are discussed in greater detail in other sections of the label: New Primary Malignancies [see Warnings and Precautions (5.1)] Hypersensitivity Reactions [see Warnings and Precautions (5.3)] Dermatologic Reactions [see Warnings and Precautions (5.4)] QT Prolongation [see Warnings and Precautions (5.5)] Hepatotoxicity [see Warnings and Precautions (5.6)] Photosensitivity [see Warnings and Precautions (5.7)] Ophthalmologic Reactions [see Warnings and Precautions (5.8)] Radiation Sensitization and Radiation Recall [see Warnings and Precautions (5.10)] Renal Failure [see Warnings and Precautions (5.11)] 6.1 Clinical Trials Experience Because clinical studies are conducted under widely varying conditions, adverse reaction rates observed in the clinical studies of a drug cannot be directly compared to rates in the clinical studies of another drug and may not predict the rates observed in a broader patient population in clinical practice. This section describes adverse drug reactions (ADRs) identified from analyses of Trial 1 and Trial 2 [see Clinical Studies (14)]. Trial 1 randomized (1:1) 675 treatment-naive patients with unresectable or metastatic melanoma to receive ZELBORAF 960 mg orally twice daily or dacarbazine 1000 mg/m2 intravenously every 3 weeks. In Trial 2, 132 patients with metastatic melanoma and failure of at least one prior systemic therapy received treatment with ZELBORAF 960 mg orally twice daily. Table 1 presents adverse reactions reported in at least 10% of patients treated with ZELBORAF. The most common adverse reactions of any grade (≥ 30% in either study) in ZELBORAF-treated patients were arthralgia, rash, alopecia, fatigue, photosensitivity reaction, nausea, pruritus, and skin papilloma. The most common (≥ 5%) Grade 3 adverse reactions were cuSCC and rash. The incidence of Grade 4 adverse reactions was ≤ 4% in both studies. The incidence of adverse events resulting in permanent discontinuation of study medication in Trial 1 was 7% for the ZELBORAF arm and 4% for the dacarbazine arm. In Trial 2, the incidence of adverse events resulting in permanent discontinuation of study medication was 3% in ZELBORAF-treated patients. The median duration of study treatment was 4.2 months for ZELBORAF and 0.8 months for dacarbazine in Trial 1, and 5.7 months for ZELBORAF in Trial 2. Table 1 Adverse Reactions Reported in ≥ 10% of Patients Treated with ZELBORAF*
Grade 4 adverse reactions limited to gamma-glutamyltransferase increased (< 1% in Trial 1 and 4% in Trial 2). Includes both squamous cell carcinoma of the skin and keratoacanthoma. Cases of cutaneous squamous cell carcinoma were required to be reported as Grade 3 per protocol. Clinically relevant adverse reactions reported in < 10% of patients treated with ZELBORAF in the Phase 2 and Phase 3 studies include: Skin and subcutaneous tissue disorders: palmar-plantar erythrodysesthesia syndrome, keratosis pilaris, panniculitis, erythema nodosum, Stevens-Johnson syndrome, toxic epidermal necrolysis Musculoskeletal and connective tissue disorders: arthritis Nervous system disorders: neuropathy peripheral, VIIth nerve paralysis Neoplasms benign, malignant and unspecified (includes cysts and polyps): basal cell carcinoma, oropharyngeal squamous cell carcinoma Infections and infestations: folliculitis Eye disorders: retinal vein occlusion Vascular disorders: vasculitis Cardiac disorders: atrial fibrillation Table 2 shows the incidence of worsening liver laboratory abnormalities in Trial 1 summarized as the proportion of patients who experienced a shift from baseline to Grade 3 or 4. Table 2 Change from Baseline to Grade 3/4 Liver Laboratory Abnormalities*
6.2 Postmarketing Experience The following adverse reactions have been identified during post approval use of ZELBORAF. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. Neoplasms benign, malignant and unspecified (incl. cysts and polyps): Progression of pre-existing chronic myelomonocytic leukemia with NRAS mutation [see Warnings and Precautions (5.1)]. Skin and subcutaneous tissue disorders: Drug reaction with eosinophilia and systemic symptoms (DRESS syndrome) [see Warnings and Precautions (5.3)]. Blood and lymphatic systems disorder: Neutropenia Injury, poisoning and procedural complications: Radiation sensitization and recall [see Warnings and Precautions (5.10)]. Gastrointestinal disorders: Pancreatitis Renal and urinary disorders: Acute interstitial nephritis, acute tubular necrosis [see Warnings and Precautions (5.11)]. 7 DRUG INTERACTIONS 7.1 Effect of Strong CYP3A4 Inhibitors or Inducers on Vemurafenib Vemurafenib is a substrate of CYP3A4 based on in vitro data; therefore, coadministration of strong CYP3A4 inhibitors or inducers may alter vemurafenib concentrations [see Clinical Pharmacology (12.3)]. Avoid coadministration of ZELBORAF with strong CYP3A4 inhibitors (e.g., ketoconazole, itraconazole, clarithromycin, atazanavir, nefazodone, saquinavir, telithromycin, ritonavir, indinavir, nelfinavir, voriconazole) or strong inducers (e.g., phenytoin, carbamazepine, rifampin, rifabutin, rifapentine, phenobarbital), and replace these drugs with alternative drugs when possible. 7.2 Effect of Vemurafenib on CYP1A2 Substrates Coadministration of ZELBORAF with tizanidine, a sensitive CYP1A2 substrate, increased tizanidine systemic exposure by 4.7-fold. Avoid concomitant use of ZELBORAF with drugs having a narrow therapeutic window that are predominantly metabolized by CYP1A2 [see Clinical Pharmacology (12.3)]. If coadministration cannot be avoided, monitor closely for toxicities and consider a dose reduction of concomitant CYP1A2 substrates. 7.3 Concurrent Ipilimumab Increases in transaminases and bilirubin occurred in a majority of patients who received concurrent ipilimumab and ZELBORAF [see Warnings and Precautions Section 5.6]. 7.4 Effect of Vemurafenib on P-gp Substrates Coadministration of ZELBORAF with digoxin, a sensitive P-glycoprotein (P-gp) substrate, increased digoxin systemic exposure by 1.8-fold. Avoid concurrent use of P-gp substrates known to have narrow therapeutic indices. If use of these medications is unavoidable, consider dose reduction of P-gp substrates with narrow therapeutic indices. 8 USE IN SPECIFIC POPULATIONS 8.1 Pregnancy Risk Summary Based on its mechanism of action, ZELBORAF can cause fetal harm when administered to a pregnant woman [see Clinical Pharmacology 12.1]. There are no available data on the use of ZELBORAF in pregnant women to determine the drug-associated risk; however, placental transfer of vemurafenib to a fetus has been reported. Exposure to vemurafenib could not be achieved in animals at levels sufficient to fully address its potential toxicity in pregnant women. Advise pregnant women of the potential harm to a fetus. The estimated background risks of major birth defects and miscarriage for the indicated population(s) are unknown. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2-4% and 15-20%, respectively. Data Animal Data Vemurafenib showed no evidence of developmental toxicity in rat fetuses at doses up to 250 mg/kg/day (approximately 1.3 times the clinical exposure at 960 mg twice daily based on AUC) or rabbit fetuses at doses up to 450 mg/kg/day (approximately 0.6 times the clinical exposure at 960 mg twice daily based on AUC). Fetal drug levels were 3–5% of maternal levels, indicating that vemurafenib has the potential to be transmitted from the mother to the developing fetus. 8.2 Lactation There is no information available regarding the presence of vemurafenib in human milk, effects on the breastfed infant, or effects on milk production. Because of the potential for serious adverse reactions in a breastfed infant, including malignancy, severe dermatologic reactions, QT prolongation, hepatotoxicity, photosensitivity, and ophthalmologic toxicity, [see Warnings and Precautions (5)], advise women not to breastfeed during treatment with ZELBORAF and for 2 weeks after the final dose. 8.3 Females and Males of Reproductive Potential Contraception Based on its mechanism of action, ZELBORAF can cause fetal harm when administered to a pregnant woman [see Use in Specific Populations (8.1)]. Advise females of reproductive potential to use effective contraception during treatment with ZELBORAF and for 2 weeks after the final dose. 8.4 Pediatric Use Safety and efficacy in pediatric patients below the age of 18 have not been established. 8.5 Geriatric Use Clinical studies of ZELBORAF did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects. 8.6 Hepatic Impairment No formal clinical study has been conducted to evaluate the effect of hepatic impairment on the pharmacokinetics of vemurafenib. No dose adjustment is recommended for patients with mild and moderate hepatic impairment based on a population pharmacokinetic analysis [see Clinical Pharmacology (12.3)]. The appropriate dose of ZELBORAF has not been established in patients with severe hepatic impairment. 8.7 Renal Impairment No formal clinical study has been conducted to evaluate the effect of renal impairment on the pharmacokinetics of vemurafenib. No dose adjustment is recommended for patients with mild and moderate renal impairment based on a population pharmacokinetic analysis [see Clinical Pharmacology (12.3)]. The appropriate dose of ZELBORAF has not been established in patients with severe renal impairment. 10 OVERDOSAGE There is no information on overdosage of ZELBORAF. 11 DESCRIPTION ZELBORAF (vemurafenib) is a kinase inhibitor available as 240 mg tablets for oral use. Vemurafenib has the chemical name propane-1-sulfonic acid {3-[5-(4-chlorophenyl)-1H-pyrrolo[2,3-b]pyridine-3-carbonyl]-2,4-difluoro-phenyl}-amide. It has the molecular formula C23H18ClF2N3O3S and a molecular weight of 489.9. Vemurafenib has the following chemical structure:
Unstratified log-rank test Total of 200 deaths (Zelboraf median follow-up 6.2 months) Hazard ratio estimated using Cox model; a hazard ratio of < 1 favors ZELBORAF Kaplan-Meier estimate Updated based on 478 deaths (Zelboraf median follow-up 13.4 months) Figure 1 Kaplan-Meier Curves of Overall Survival – Treatment-Naïve Patients
Kaplan-Meier estimate Patients with Wild-Type BRAF Melanoma ZELBORAF has not been studied in patients with wild-type BRAF melanoma [see Warnings and Precautions (5.2)]. 16 HOW SUPPLIED/STORAGE AND HANDLING ZELBORAF (vemurafenib) is supplied as 240 mg film-coated tablets with VEM debossed on one side. The following packaging configurations are available: NDC 50242-090-01 single bottle of 120 count NDC 50242-090-02 single bottle of 112 count Storage and Stability: Store at room temperature 20°C–25°C (68°F–77°F); excursions permitted between 15°C and 30°C (59°F and 86°F), See USP Controlled Room Temperature. Store in the original container with the lid tightly closed. Disposal of unused/expired medicines: The release of pharmaceuticals in the environment should be minimized. Medicines should not be disposed of via wastewater and disposal through household waste should be avoided. Use established "collection systems," if available in your location. 美国药物管理局FDA批准Zelboraf治疗黑色素瘤 8月17日，美国食品和药物管理局FDA批准Zelboraf(vemurafenib)用于治疗晚期转移性或不能切除的黑色素瘤。此药是今年获准的第二个治疗黑色素瘤的药物，它能改善患者的总体生存期。 Zelboraf特别适用于治疗有基因BRAF V600E突变的黑色素瘤。该药尚未在该突变阴性的黑色素瘤病人中进行过研究。 Zelboraf获准的同时，FDA还批准了首个用于检测cobas 4800 BRAF V600突变的试验方法，这一诊断方法将有助于确定病人的黑色素瘤细胞是否存在BRAF V600E突变。 BRAF蛋白通常涉及调节细胞生长，但它在约半数晚期黑色素瘤病人中发生突变。Zelboraf是BRAF抑制剂，能阻断V600E发生突变的BRAF蛋白的功能。 “Zelboraf是FDA批准的第二个治疗黑色素瘤的新药，该药被证明能改善病人的总生存。” FDA药物评价与研究中心肿瘤药物产品办公室主任理查（Richard Pazdur）说：“FDA在3月批准的Yervoy (伊匹木单抗，ipilimumab)，是另一种治疗晚期黑色素瘤的新药，也显示能延长病人的生存期。” Zelboraf通过了FDA的优先评审项目审查。一项国际化研究确定了Zelboraf的安全性和有效性，该研究纳入675例有晚期黑色素瘤伴BRAF V600E突变病人，这些病人以前未经治疗。病人分别接受Zelboraf或达卡巴嗪治疗，试验设计的测定指标是总生存期。 Zelboraf组病人未达到中位生存期（77%病人仍生存），达卡巴嗪组病人的中位生存期为8个月（64%仍生存）。 FDA体外诊断设备评价与安全办公室主任Alberto Gutierrez说：“今日批准的Zelboraf和cobas检测，是一个很好的范例，表明可同时研发伴随诊断，确保病人在一种安全的方式下接受高效、更个体化的治疗。” FDA批准cobas 4800 BRAF V600突变检测法，是基于临床研究的数据，该研究也评估了Zelboraf的安全性和有效性。黑色素瘤病人的组织标本被采集来检测该突变。 Zelboraf组病人最常报告的副作用包括关节痛、皮疹、脱发、疲乏、恶心以及皮肤对日光敏感。大约26%的病人发生了可手术治疗的皮肤鳞状细胞癌。所以，接受Zelboraf治疗的病人应避免日晒。Zelboraf的用药指引告知医务人员和病人有关Zelboraf的潜在风险。 EJM：Zelboraf使黑色素瘤平均生存期延长至16个月 晚期黑色素瘤患者口服靶向治疗药物vemurafenib，可获得16个月的平均生存期，而转移性黑色素瘤病人以往的存活期一般为6到10个月。 vemurafenib刚在本周被欧洲批准，被美国批准是在11年的8月份，同时也在巴西、加拿大、以色列和新西兰被批准上市。 这些新的生存期数据来自于对该药物的长期数据观察——一项开放性的2期临床试验，包括132名BRAF阳性的晚期黑色素瘤病人。Sosman等写到，研究中长期随访关于vemurafenib vs.dacarbazine总生存期的结果还未在3期试验中显示。 总生存期是2期试验的次要终点，在美国的10个中心和澳大利亚的3个中心进行。主要终点是总体反应率，结果为53%（完全反应，6%；部分反应，47；95%CI，44-62）。上述反应率证实了1期反应的发现，最早是在2010年黑色素瘤研究学会国际研究大会上报告。 尽管总体反应率与2010年大会相比没什么变化，但是总体生存期数据更加成熟了：平均总体生存期为15.9个月；6个月的总体生存率为77%，12个月为58%，18个月为43%。 这些病人的身体基线水平比较差，与其他大型的2期和3期试验的人群相比，61%有MIc期疾病，49%的乳酸脱氢酶水平升高。BRAF突变具有一种生存劣势，突变与转移性疾病病人生存期缩短具有相关性。 一些病人在随访期接受了额外的治疗，有32个病人（24%）vemurafenib治疗疾病进展后接受了 ipilimumab。在非计划的事后分析中，排除了这32个病人，总体生存期保持在15.9个月。 本研究中，病人接受的平均剂量为1740mg/天。不幸的是，对vemurafenib的反应是不持久的，中位反应持续时间为6.7个月，中位无进展生存期为6.8个月。没有反应，意味着对药物产生抗性，病人需要使用其他药物治疗。 最常见的不良事件是1或2级的关节痛、皮疹、光敏、疲劳和脱发。26%的病人被诊断出皮肤鳞状细胞癌，通常为1级病变（20个病人）或2级病变（6个病人）。发展到皮肤鳞状细胞癌后角化棘皮病的平均时间为8周。这些继发的皮肤肿瘤与黑色素瘤比较起来相对良性，没有理由停止vemurafenib，该观点来自新英格兰上个月的一篇述评。 但是，根据一篇同期述评，使用vemurafenib治疗的病人应该检测RAS突变，该突变通常会发生在这种继发的肿瘤中。这些检测会告诉医生哪些病人具有RAS驱动的继发肿瘤，这些检测非常重要，因为RAS突变可以在除了皮肤之外导致肿瘤，例如肺部。但是，迄今为止，还没有证据表明vemurafenib可触发RAS驱动的其他器官发生肿瘤。 完整使用资料附件：https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=38eea320-7e0c-485a-bc30-98c3c45e2763 | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
