Cotellic(cobimetinib 中文译名：考比替尼)口服片是罗氏公司近期开发的一款口服靶向抗癌新药，获美国FDA及欧盟批准，联合罗氏自身已上市的抗癌药Zelboraf（vemurafenib，威罗菲尼），用于BRAF V600E或V600K突变阳性、不可切除性或转移性黑色素瘤患者的治疗。 Cobimetinib是一种口服小分子MEK抑制剂，MEK是一种蛋白激酶，是RAS-RAF-MEK-ERK信号通路的一部分，该通路可促进细胞的分裂和存活，在人类癌症（包括黑色素瘤）中往往处于激活状态。cobimetinib旨在选择性阻断MEK蛋白的活性，从而阻断其下游的信号通路传导。 FDA的药品评价和研究中心中血液学和肿瘤产品室主任Richard Pazdur，M.D.说：“因为我们肿瘤生物学知识的继续进展，我们已学习到癌细胞有明显的能力适应和成为对靶向治疗耐药。联合两种或更多治疗应付不同癌-所致靶点可能有助于解决这个挑战，” “今天的批准提供一个新靶向治疗，当添加至威罗菲尼，证实在有BRAF突变-阳性黑色素瘤患者比单独威罗菲尼更大获益。”优先审评，孤儿药物指定 批准日期：2015年11月10日；公司：Genentech有限公司 COTELLIC(考比替尼[cobimetinib])片，供口服使用 美国初次批准：2015 作用机制 Cobimetinib是一种丝裂原活化蛋白激酶(MAPK)的可逆性抑制剂/细胞外信号调节激酶 1(MEK1)和MEK2。MEK蛋白是细胞外信号相关激酶(ERK)通路上游调节剂，它促进细胞增殖。BRAF V600E和K突变导致BRAF通路其中包括MEK1和MEK2的组成性激活。在植入表达BRAF V600E肿瘤细胞系中，cobimetinib抑制肿瘤细胞生长。 Cobimetinib和威罗菲尼靶向在RAS/RAF/MEK/ERK通路两个不同的激酶。与任一个单药比较，在体外cobimetinib和威罗菲尼的共同给药导致增高的凋亡和在小鼠植入隐藏BRAF V600E 突变肿瘤细胞系减慢肿瘤生长。在一个体内小鼠植入模型Cobimetinib还阻止威罗菲尼-介导的野生型BRAF肿瘤细胞系生长增强。 适应证和用途 COTELLIC是一种激酶抑制剂适用为患者有不能切除或转移黑色素瘤有一个BRAF V600E或V600K突变，与威罗菲尼联用的治疗。 使用限制：COTELLIC不适用为有野生型BRAF黑色素瘤患者的治疗。. 剂量和给药方法 ⑴  COTELLIC的开始治疗前确证在肿瘤标本中BRAF V600E或V600K突变的存在。 ⑵  推荐剂量是对每个28-天疗程的头21天60 mg口服每天1次直至疾病进展或不可接受毒性。有或无食物服用COTELLIC。 剂型和规格 片：20mg 禁忌证 无。 警告和注意事项 ⑴  新原发恶性病，皮肤和非-皮肤：治疗开始前，当用治疗时,和直至COTELLIC末次剂量后共至6个月对新恶性病监视患者。 ⑵  出血：用COTELLIC可能发生重大出血事件监视出血的体征和症状。 ⑶  心肌病：在接受COTELLIC与威罗菲尼患者比较用威罗菲尼作为单药心肌病的风险增加。.尚未在左室射血分量(LVEF)减低患者中确定COTELLIC的安全性。治疗前，用COTELLIC治疗期间治疗后1个月，然后其后每3个月评价LVEF。 ⑷  严重皮肤学反应：监视严重皮疹。中断, 减低，或终止COTELLIC。 ⑸  严重视网膜病和视网膜静脉阻塞：在有规则间隔进行眼科学检查和对任何视觉障碍。对视网膜静脉阻塞(RVO)永久地终止COTELLIC。 ⑹  肝毒性：治疗期间和当临床上指示时监视肝实验室测试。 ⑺  横纹肌溶解综合证：监视肌酸磷酸激酶定期地和当临床上指示为横纹肌溶解综合证体征和症状。 ⑻ 严重光敏感性：忠告患者避免日光暴露。 ⑼ 胚胎-胎儿毒性：可能致胎儿危害。 忠告生殖潜能女性对胎儿潜在风险和使用有效避孕。 不良反应 对COTELLIC最常见不良反应(≥20%)是腹泻, 光敏反应，恶心，发热，和呕吐。最常见(≥5%) 3-4级实验室异常是增高的GGT，增高的CPK，低磷血症，增高的ALT，淋巴细胞减少，增高的AST，增高的碱性磷酸酶，低钠血症。 药物相互作用 避免COTELLIC与强或中度CYP3A诱导剂或抑制剂的同时给药。 特殊人群中使用 哺乳：当用COTELLIC时不要哺乳喂养。 供应/贮存和处置 COTELLIC(cobimetinib)以20 mg膜包衣片在一侧凹陷有“COB”供应。 可得到在63片瓶中COTELLIC片。 NDC 50242-717-01 贮存和稳定性：贮存在室温低于30°C(86°F)。 Cobimetinib (Cotellic Tablets) INDICATIONS AND USAGE COTELLIC (cobimetinib) is indicated for the treatment of patients with unresectable or metastatic melanoma with a BRAF V600E or V600K mutation, in combination with ZELBORAF® (vemurafenib). Limitation of Use: COTELLIC is not indicated for treatment of patients with wild-type BRAF melanoma. IMPORTANT SAFETY INFORMATION WARNINGS AND PRECAUTIONS Review the Full Prescribing Information for ZELBORAF for information on the serious risks of ZELBORAF. New Primary Malignancies New primary malignancies, cutaneous and non-cutaneous, can occur with COTELLIC. Cutaneous Malignancies •In Trial 1, the following cutaneous malignancies or premalignant conditions occurred in the COTELLIC with ZELBORAF arm and the ZELBORAF arm, respectively: cutaneous squamous cell carcinoma (cuSCC) or keratoacanthoma (KA) (6% and 20%), basal cell carcinoma (4.5% and 2.4%), and second primary melanoma (0.8% and 2.4%). Among patients receiving COTELLIC with ZELBORAF, the median time to detection of first cuSCC/KA was 4 months (range: 2 to 11 months), and the median time to detection of basal cell carcinoma was 4 months (range: 27 days to 13 months). The time to onset in the 2 patients with second primary melanoma was 9 months and 12 months •Perform dermatologic evaluations prior to initiation of therapy and every 2 months while on therapy. Manage suspicious skin lesions with excision and dermatopathologic evaluation. No dose modifications are recommended for COTELLIC. Conduct dermatologic monitoring for 6 months following discontinuation of COTELLIC when administered with ZELBORAF Non-cutaneous Malignancies •Based on its mechanism of action, ZELBORAF may promote growth and development of malignancies. In Trial 1, 0.8% of patients in the COTELLIC with ZELBORAF arm and 1.2% of patients in the ZELBORAF arm developed non-cutaneous malignancies •Monitor patients receiving COTELLIC, when administered with ZELBORAF, for signs or symptoms of non-cutaneous malignancies Hemorrhage Hemorrhage, including major hemorrhages defined as symptomatic bleeding in a critical area or organ, can occur with COTELLIC •In Trial 1, the incidence of grade 3-4 hemorrhages was 1.2% in patients receiving COTELLIC with ZELBORAF and 0.8% in patients receiving ZELBORAF. Hemorrhage (all grades) was 13% in patients receiving COTELLIC with ZELBORAF and 7% in patients receiving ZELBORAF. Cerebral hemorrhage occurred in 0.8% of patients receiving COTELLIC with ZELBORAF and in none of the patients receiving ZELBORAF. Gastrointestinal tract hemorrhage (3.6% vs 1.2%), reproductive system hemorrhage (2.0% vs 0.4%), and hematuria (2.4% vs 0.8%) also occurred at a higher incidence in patients receiving COTELLIC with ZELBORAF compared with patients receiving ZELBORAF •Withhold COTELLIC for grade 3 hemorrhagic events. If improved to grade 0 or 1 within 4 weeks, resume COTELLIC at a lower dose level. Discontinue COTELLIC for grade 4 hemorrhagic events and any grade 3 hemorrhagic events that do not improve Cardiomyopathy •Cardiomyopathy, defined as symptomatic and asymptomatic decline in left ventricular ejection fraction (LVEF), can occur with COTELLIC. The safety of COTELLIC has not been established in patients with a baseline LVEF that is either below institutional lower limit of normal (LLN) or below 50% •In Trial 1, patients were assessed for decreases in LVEF by echocardiograms or MUGA at baseline, Week 5, Week 17, Week 29, Week 43, and then every 4 to 6 months thereafter while receiving treatment. Grade 2-3 decrease in LVEF occurred in 26% of patients receiving COTELLIC with ZELBORAF and 19% of patients receiving ZELBORAF. The median time to first onset of LVEF decrease was 4 months (range: 23 days to 13 months). Of the patients with decreased LVEF, 22% had dose interruption and/or reduction and 14% required permanent discontinuation. Decreased LVEF resolved to above the LLN or within 10% of baseline in 62% of patients receiving COTELLIC with a median time to resolution of 3 months (range: 4 days to 12 months) •Evaluate LVEF prior to initiation, 1 month after initiation, and every 3 months thereafter until discontinuation of COTELLIC. Manage events of left ventricular dysfunction through treatment interruption, reduction, or discontinuation. In patients restarting COTELLIC after a dose reduction or interruption, evaluate LVEF at approximately 2 weeks, 4 weeks, 10 weeks, and 16 weeks, and then as clinically indicated Severe Dermatologic Reactions Severe rash and other skin reactions can occur with COTELLIC. •In Trial 1, grade 3 to 4 rash occurred in 16% of patients receiving COTELLIC with ZELBORAF and in 17% of patients receiving ZELBORAF, including grade 4 rash in 1.6% of patients receiving COTELLIC with ZELBORAF and 0.8% of the patients receiving ZELBORAF. The incidence of rash resulting in hospitalization was 3.2% in patients receiving COTELLIC with ZELBORAF and 2.0% in patients receiving ZELBORAF. In patients receiving COTELLIC, the median time to onset of grade 3 or 4 rash events was 11 days (range: 3 days to 2.8 months). Among patients with grade 3 or 4 rash events, 95% experienced complete resolution, with the median time to resolution of 21 days (range: 4 days to 17 months) •Interrupt, reduce the dose, or discontinue COTELLIC for severe dermatologic reactions Serous Retinopathy and Retinal Vein Occlusion Ocular toxicities can occur with COTELLIC, including serous retinopathy (fluid accumulation under layers of the retina). •In Trial 1, ophthalmologic examinations, including retinal evaluation, were performed pretreatment and at regular intervals during treatment. Symptomatic and asymptomatic serous retinopathy was identified in 26% of patients receiving COTELLIC with ZELBORAF. The majority of these events were reported as chorioretinopathy (13%) or retinal detachment (12%). The time to first onset of serous retinopathy events ranged from 2 days to 9 months. The reported duration of serous retinopathy ranged from 1 day to 15 months. One patient in each arm developed retinal vein occlusion •Perform an ophthalmologic evaluation at regular intervals and any time a patient reports new or worsening visual disturbances. If serous retinopathy is diagnosed, interrupt COTELLIC until visual symptoms improve. Manage serous retinopathy with treatment interruption, dose reduction, or with treatment discontinuation Hepatotoxicity Hepatotoxicity can occur with COTELLIC. •The incidences of grade 3-4 liver laboratory abnormalities in Trial 1 among patients receiving COTELLIC with ZELBORAF compared with patients receiving ZELBORAF were 11% vs 6% for alanine aminotransferase, 7% vs 2.1% for aspartate aminotransferase, 1.6% vs 1.2% for total bilirubin, and 7% vs 3.3% for alkaline phosphatase. Concurrent elevation in ALT >3x the upper limit of normal (ULN) and bilirubin >2x ULN in the absence of significant alkaline phosphatase >2x ULN occurred in one patient (0.4%) receiving COTELLIC with ZELBORAF and no patients receiving single-agent ZELBORAF •Monitor liver laboratory tests before initiation of COTELLIC and monthly during treatment, or more frequently as clinically indicated. Manage grade 3-4 liver laboratory abnormalities with dose interruption, reduction, or discontinuation of COTELLIC Rhabdomyolysis Rhabdomyolysis can occur with COTELLIC. •In Trial 1, grade 3-4 CPK elevations, including asymptomatic elevations over baseline, occurred in 12% of patients receiving COTELLIC with ZELBORAF and 0.4% of patients receiving ZELBORAF. The median time to first occurrence of grade 3-4 CPK elevations was 16 days (range: 12 days to 11 months) in patients receiving COTELLIC with ZELBORAF; the median time to complete resolution was 15 days (range: 9 days to 11 months). Elevation of serum CPK increase of more than 10x the baseline value with a concurrent increase in serum creatinine of 1.5x or greater compared with baseline occurred in 3.6% of patients receiving COTELLIC with ZELBORAF and in 0.4% of patients receiving ZELBORAF •Obtain baseline serum CPK and creatinine levels prior to initiating COTELLIC, periodically during treatment, and as clinically indicated. If CPK is elevated, evaluate for signs and symptoms of rhabdomyolysis or other causes. Depending on the severity of symptoms or CPK elevation, dose interruption or discontinuation of COTELLIC may be required Severe Photosensitivity Photosensitivity, including severe cases, can occur with COTELLIC. •In Trial 1, photosensitivity was reported in 47% of patients receiving COTELLIC with ZELBORAF: 43% of patients with Grades 1 or 2 photosensitivity and the remaining 4% with Grade 3 photosensitivity. Median time to first onset of photosensitivity of any grade was 2 months (range: 1 day to 14 months) in patients receiving COTELLIC with ZELBORAF, and the median duration of photosensitivity was 3 months (range: 2 days to 14 months). Among the 47% of patients with photosensitivity reactions on COTELLIC with ZELBORAF, 63% experienced resolution of photosensitivity reactions. •Advise patients to avoid sun exposure, wear protective clothing, and use a broad-spectrum UVA/UVB sunscreen and lip balm (SPF ≥30) when outdoors. Manage intolerable grade ≥2 photosensitivity with dose modifications Embryo-Fetal Toxicity •Based on its mechanism of action and findings from animal reproduction studies, COTELLIC can cause fetal harm when administered to a pregnant woman. In animal reproduction studies, oral administration of cobimetinib in pregnant rats during the period of organogenesis was teratogenic and embryotoxic at doses resulting in exposures (area under the curves [AUCs]) that were 0.9 to 1.4 × those observed in humans at the recommended human dose of 60 mg •Advise pregnant women of the potential risk to a fetus. — Advise females of reproductive potential to use effective contraception during treatment with COTELLIC and for 2 weeks following the final dose of COTELLIC — Advise women of childbearing potential and men to use appropriate contraceptive measures during ZELBORAF therapy and for at least 2 months after discontinuation of ZELBORAF Most Common Adverse Reactions for COTELLIC •The most common (≥20%) adverse reactions with COTELLIC were diarrhea, photosensitivity reaction, nausea, pyrexia and vomiting. The most common (≥5%) grade 3-4 laboratory abnormalities are increased GGT, increased CPK, hypophosphatemia, increased ALT, lymphopenia, increased AST, increased alkaline phosphatase, and hyponatremia http://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=c387579e-cee0-4334-bd1e-73f93ac1bde6