FDA顾问小组全票拒绝批准肝转移性黑色素瘤药物设备Melblez Kit

美国食品药品管理局（FDA）的一个顾问小组认为，使用药物设备组合Melblez Kit直接将美法仑（左旋溶肉瘤素）输送到肝转移性葡萄膜恶性黑色素瘤患者的肝脏内，其风险超过任何可能的治疗收益，顾问小以16比0的投票结果拒绝批准该药物设备。
在FDA的一次肿瘤药物顾问委员会上，几位专家小组成员表示，这种药物设备很有前途，但考虑到它明显的毒性以及对总生存期缺乏影响，这种药物设备仍需要进行试验研究。
Melblez Kit是美法仑与Delcath肝脏输送系统组成的一种药物设备，其中肝脏输送系统由两根医用导管和一个体外血液滤过组件组成。根据生产厂家Delcath Systems提供的信息，医用导管用于将高剂量化疗药物经肝动脉直接输送入肝脏，而体外血液滤过组件在血液返回体循环之前降低血液中的药物浓度。进行此项程序需要患者住院大约4天的时间，整个操作过程需要全身麻醉，大约花费3小时，并且两次操作要间隔4周的时间。
目前还没有FDA批准的用于不可切除的肝转移性黑色素瘤治疗的方法。这种药物设备可以视为一种抗肿瘤方式，但同时这种方式也与致命的、威胁生命的副作用联系在一起。这种药物设备有一种不利于患者生存的趋势，公司提出的用来处理那些风险因素的风险评估和减灾战略(REMS)“不会改进所观察到的效益风险属性，” FDA血液和肿瘤产品办公室的一位卫生官员杰弗里·金博士这样对顾问小组说。
2006年至2010年在美国进行的一项开放性随机多中心III期临床研究中，该药物设备被用来治疗44位患者。这些患者的治疗结果与49名相匹配的给予最佳替代护理(BAC) 的患者结果进行了对比。所有患者均患有手术不能切除的肝转移性黑色素瘤或皮肤黑色素瘤（89%的患者有葡萄膜恶性黑色素瘤，几乎一半的患者在美国国家癌症中心进行治疗）。受试者在其肝脏疾病进展时进行治疗。Melblez Kit的给药剂量为3.0 mg/kg，平均治疗三个周期，每周期平均120天；最佳替代护理包括49%的患者全身化疗和22%的患者肝内化疗。
根据公司提供的信息，试验研究的主要临床疗效指标，肝脏无进展生存期(hPFS)中值在药物设备治疗患者中是7个月，最佳替代护理患者为1.6个月，具有统计学意义的显著性差异，也代表风险降低61%（风险比率为0.39）。药物设备治疗患者的总无进展生存期中值为4.8个月，最佳替代护理患者为1.6个月，也具有统计学意义的显著性差异。
两者的总生存期基本一致：药物设备治疗组为9.8个月，最佳替代护理组为9.9个月。但几乎80%的Melblez Kit治疗患者有严重不良事件，几乎70%的患者有4级不良事件。而最佳替代护理患者的严重不良事件发生率为16%，4级不良事件发生率为2%。最佳替代护理患者没有出现因不良事件而死亡的情况。但有3名药物设备治疗患者因不良事件而死亡。
与黑色素瘤相关的拓展阅读：

• JCI：黑色素瘤转移有关的血氧调控因子SRC蛋白被发现
• 默沙东黑色素瘤药物Lambrolizumab获FDA“突破性疗法”资格
• JCO：新研究揭示转移性黑色素瘤对威罗菲尼的耐药机制
• JNCI：PAK1抑制剂能有效治疗BRAF野生型黑色素瘤患者
• Cancer：阿司匹林可降低黑色素瘤发病风险
• NAT GENET ：肥胖基因或是黑色素瘤的风险因素
更多信息请点击：有关黑色素瘤更多资讯

FDA advisory panel nixes approval of drug-device for liver metastases
The risks outweigh any possible benefits of treatment with a drug-device combination that delivers melphalan directly to the livers of patients with liver metastases from ocular melanoma, a Food and Drug Administration advisory panel concluded in a 16-0 vote.
At a meeting of the FDA’s Oncologic Drugs Advisory Committee, several panelists said that the treatment was promising but should remain investigational, given its marked toxicity and lack of effect on overall survival.
The Melblez Kit is a combination of melphalan and the Delcath Hepatic Delivery System, which includes two catheters and an extracorporeal hemofiltration component. The catheter is used to administer high doses of the chemotherapy drug directly to the liver via the hepatic artery, and the hemofiltration component lowers the drug level before the blood is returned to the systemic circulation, according to the manufacturer, Delcath Systems. Patients are hospitalized for about 4 days for the procedure, which takes about 3 hours and is performed at 4-week intervals under general anesthesia.
There are no FDA-approved treatments for patients with unresectable metastatic ocular melanoma to the liver, which is the indication under FDA review.
Treatment with the kit was associated with antitumor activity, but it also was associated with fatal and life-threatening adverse reactions. There was a trend towards a detrimental effect on survival, and the risk evaluation and mitigation strategy (REMS) proposed by the company to address those risks "will not improve the observed benefit-risk profile," Dr. Geoffrey Kim, a medical officer in the FDA’s office of hematology and oncology products, told the panel.
In an open-label, randomized multicenter phase-III study conducted between 2006 and 2010 in the United States, the device was used to treat 44 patients. Their outcomes were compared with those of 49 matched patients given the best alternative care (BAC). All patients had surgically unresectable hepatic-dominant metastatic ocular or cutaneous melanoma (89% had ocular melanoma, and almost half were treated at the National Cancer Institute). Subjects were treated until their hepatic disease progressed. The dose administered with the Melblez Kit was 3.0 mg/kg for a median of three treatment cycles and a median of 120 days; best alternative care included systemic chemotherapy in 49% of patients and intrahepatic chemotherapy in 22%.
The primary end point, median hepatic progression-free survival (hPFS) was 7 months among those on the device, compared with 1.6 months among those on BAC, a statistically significant difference that represented a 61% reduction in risk (hazard ratio, 0.39), according to the company. The median overall PFS was 4.8 months among those treated with the device, compared with 1.6 months among those on BAC, also a statistically significant difference. {nextpage}
Overall survival was comparable: 9.8 months in the device-treated group and 9.9 months in those on best alternative care. Further, almost 80% of patients in the Melblez Kit arm had a serious adverse event and almost 70% had a grade-4 adverse event. With best alternative care, the rate of serious adverse events was 16% and the rate of grade-4 events was 2%. No patients on best alternative care died because of an adverse event. Three patients treated with the drug-device died from adverse events.
The adverse reactions in a combined population of 121 patients in the phase-III and phase-II studies and in 28 patients in the BAC arm who crossed over to treatment with the device included toxic deaths in 7% (including cases of hepatic failure, streptococcal sepsis, and GI hemorrhage), cerebral infarction in 4%, MI in 2%, and grade-4 bone marrow suppression with a median time to recovery of more than 1 week in more than 70%. About half had to be rehospitalized for an adverse event.
For a cancer treatment, this safety profile "is unprecedented, in terms of the toxicity," Dr. Richard Pazdur, director of the FDA’s office of hematology and oncology products, remarked.
After the vote, panel member Dr. Louis Diehl, professor of medicine at Duke University, Durham, N.C., said that progression-free survival is valued in studies as an indicator of improved quality of life and it can be an early marker of increased survival. "Unfortunately, this treatment has an increase in morbidity and an increase in mortality and I can’t see from the survival curve that it will ever translate into an improvement in survival."
Delcath did not issue a response after the panel’s vote.
The FDA usually follows the recommendations of its advisory panels. Panelists have been cleared of potential conflicts of interest related to the topic of the meeting, although a panelist may occasionally be given a waiver. At this meeting, two panelists who had expertise in the topic were given waivers (one panelist is the principal investigator in a study of a competing device and the other works at a medical center where a study of a competing device is being conducted).
About 2,000 cases of ocular melanoma are diagnosed annually in the United States and about 50% metastasize, most often to the liver, according to Delcath. In Europe and Australia, the company markets the device for a broad range of liver metastases, not just those caused by ocular melanoma, according to the company.