黑色素瘤靶向药及伴随诊断试剂：Braftovi+Mektovi组合疗法，为临床治疗新标准.
2018年6月28日，Array BioPharma公司宣布，美国食品和药物管理局（FDA）已批准Braftovi（binimetinib，一种MEK抑制剂）胶囊联合Mektovi（encorafenib，一种BRAF抑制剂）片剂，用于经FDA批准的一种检测方法证实存在BRAF V600E或BRAF V600K突变的不可切除性或转移性黑色素瘤患者的治疗。值得注意的是，Braftovi不适用于野生型BRAF黑色素瘤的治疗。
  此次批准也是Braftovi+Mektovi组合方案的首个监管批准，该方案上市后，将在晚期BRAF突变黑色素瘤细分市场，主要针对诺华公司的Tafinlar+Mekinist方案展开竞争。华尔街知名投行Jefferies认为，在这一细分市场，Braftovi+Mektovi组合方案可以比诺华的组合方案做的更好，后者在该市场的年销售额额大约为4亿美元。
  MEK和BRAF是MAPK信号通路（RAS-RAF-MEK-ERK）中的关键蛋白激酶。研究表明，这一通路调节了包括细胞增殖、分化、存活、血管生成在内的多种关键细胞活动。在许多癌症中，如黑色素瘤、结直肠癌和甲状腺癌，这一信号通路中的蛋白质已被证实异常激活。
  binimetinib是一种MEK抑制剂，encorafenib则是一种BRAF抑制剂，这2种药物均靶向该信号通路中的关键酶。目前，Array也正在评估binimetinib和encorafenib治疗其他类型癌症的潜力，包括BRAF突变结直肠癌。
  Braftovi+Mektovi组合方案的获批，是基于III期临床研究COLUMBUS的结果。数据显示，与罗氏黑的晚期色素瘤特效药Zelboraf（vemurafenib，威罗菲尼）相比，Braftovi+Mektovi组合方案无进展生存期延长了一倍（中位PFS：14.9个月 vs 7.3个月，HR=0.54，95%CI:0.41-0.71，p＜0.0001）。该研究中，Braftovi+Mektovi方案组仅有5%的患者因不良反应停止治疗，该方案组最常见的不良反应（≥25%）为疲劳、恶心、腹泻、呕吐、腹痛和关节痛。
  今年2月公布的COLUMBUS研究总生存期（OS）分析数据显示，与Zelboraf（960mg，每日一次）相比，Braftovi+Mektovi方案显著降低了死亡风险（HR=0.61，95%CI:0.47-0.79，p＜0.0001）：Zelboraf单药组中位OS为16.9个月，Braftovi+Mektovi方案组中位OS为33.6个月。这些积极数据进一步增强了BRAF/MEK抑制剂组合疗法的临床证据。
  黑色素瘤基金会主席Valerie Guild评论称，Braftovi+Mektovi方案是治疗BRAF突变黑色素瘤在III期临床中生存期超过30个月的首个靶向疗法，代表着BRAF突变黑色素瘤的一种新的临床护理保准。鉴于有近一半的确诊为转移性黑色素瘤的患者检测到了BRAF突变，Braftovi+Mektovi方案的获批，对黑色素瘤患者群体而言将是一个莫大的好消息，将满足该类患者群体中存在的一个关键未满足医疗需求。

BRAFTOVI(encorafenib)+MEKTOVI(binimetinib)
1.BRAFTOVI (encorafenib) capsules
BRAFTOVI Rx
Generic Name and Formulations:
Encorafenib 50mg, 75mg; caps.
Company:
Array BioPharma, Inc.
Indications for BRAFTOVI:
In combination with binimetinib, for unresectable or metastatic melanoma with a BRAF V600E or V600K mutation, as detected by an FDA-approved test.
Limitations Of use:
Not for treatment of wild-type BRAF melanoma.
Adult:
Confirm BRAF V600E or V600K mutation prior to initiation. 450mg once daily with binimetinib until disease progression or unacceptable toxicity. Concomitant strong or moderate CYP3A4 inhibitors including grapefruit juice: avoid; if unavoidable, reduce Braftovi dose by ⅓ (if strong inhibitor) or by ½ (if moderate inhibitor). Dose modifications for adverse reactions: see full labeling. Refer to binimetinib labeling for dosing.
Children:
Not established.
Warnings/Precautions:
Monitor for new primary malignancies (cutaneous, non-cutaneous). Perform dermatologic exams prior to initiating, every 2 months during, and up to 6 months following treatment discontinuation. Discontinue if RAS-mutation (+) non-cutaneous malignancies develop. Uveitis: assess for visual symptoms at each visit; perform ophthalmologic exams regularly and for new or worsening visual disturbances. Long QT syndromes, significant bradyarrhythmias, severe or uncontrolled heart failure, concomitant drugs associated with QT prolongation; monitor. Correct hypokalemia and hypomagnesemia prior to and during treatment. Withhold, reduce or permanently discontinue dose if QTc >500ms. Increased risk of certain adverse reactions with Braftovi monotherapy; reduce dose if binimetinib interrupted or discontinued; see full labeling. Embryo-fetal toxicity. Pregnancy: exclude status prior to initiation. Females of reproductive potential should use effective contraception (non-hormonal methods) during and for 2 weeks after final dose. Nursing mothers: not recommended (during and for 2 weeks after final dose).
Pharmacological Class:
Kinase inhibitor.
Interactions:
Potentiated by strong or moderate CYP3A4 inhibitors including grapefruit juice; avoid (see Adult). Antagonized by strong or moderate CYP3A4 inducers; avoid. May antagonize hormonal contraceptives; avoid. May affect sensitive CYP3A4 substrates. Avoid concomitant drugs known to prolong QT/QTc interval.
Adverse Reactions:
In combination with binimetinib: fatigue, nausea, vomiting, abdominal pain, arthralgia; hemorrhage.
Generic Availability:
NO
How Supplied:
Caps 50mg—60; 75mg—90
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2.Mektovi(Binimetinib Tablets)
MEKTOVI Rx
Generic Name and Formulations:
Binimetinib 15mg; tabs.
Company:
Array BioPharma, Inc.
Select therapeutic use: Melanoma and other skin cancers
Indications for MEKTOVI:
In combination with encorafenib, for unresectable or metastatic melanoma with a BRAF V600E or V600K mutation, as detected by an FDA-approved test.
Adult:
Confirm BRAF V600E or V600K mutation prior to initiation. 45mg twice daily (approx. 12hrs apart) with encorafenib until disease progression or unacceptable toxicity. Moderate or severe hepatic impairment: 30mg twice daily. Dose modifications for adverse reactions: see full labeling. Refer to encorafenib labeling for dosing. Discontinue if encorafenib is permanently discontinued.
Children:
Not established.
Warnings/Precautions:
Cardiomyopathy: assess LVEF prior to initiating, 1 month after initiation, and then every 2–3 months during treatment. Patients with baseline LVEF below 50% or LLN: not established. Cardiovascular risk factors; monitor closely. Venous thromboembolism (DVT & PE). Ocular toxicities (serious retinopathy, retinal vein occlusion [RVO], uveitis): assess for visual symptoms at each visit; perform ophthalmologic exams regularly and for new or worsening visual disturbances (esp. within 24hrs for RVO). Assess new or progressive unexplained pulmonary symptoms or for possible interstitial lung disease. Hepatotoxicity: monitor liver tests before initiation, monthly during treatment, and as clinically indicated. Rhabdomyolysis: monitor CPK and creatinine prior to initiating, periodically during, and as clinically indicated. Embryo-fetal toxicity. Pregnancy: exclude status prior to initiation. Females of reproductive potential should use effective contraception during and for ≥30 days after final dose. Nursing mothers: not recommended (during and for 3 days after final dose).
Pharmacological Class:
Kinase inhibitor.
Adverse Reactions:
In combination with encorafenib: fatigue, nausea, diarrhea, vomiting, abdominal pain; hemorrhage.
Generic Availability:
NO
How Supplied:
Tabs—180