FDA批准帕妥珠单抗用于转移性HER2+乳腺癌

 

随着美国食品药品管理局(FDA)6月8日批准帕妥珠单抗作为一线治疗，HER2阳性转移性乳腺癌女性患者得到了一把双刃剑。

 

在标准的曲妥珠单抗+多西他赛化疗基础上加用新型HER2阻断剂帕妥珠单抗，可延长这类患者的无进展生存期。目前还未获得总生存方面的数据。

帕妥珠单抗是一种人源化单克隆抗体，由罗氏子公司基因泰克通过生物工程方法制备而成。该药还能阻断其他的HER家族成员，包括EGFR、HER3和HER4，据称可补充曲妥珠单抗的HER2抑制作用。曲妥珠单抗也是由基因泰克和罗氏生产的。

这一批准令在很大程度是基于CLEOPATRA(帕妥珠单抗与曲妥珠单抗的临床评估)试验的结果。双重HER2阻断可使中位无进展生存期从标准化疗对照组的12.4个月增至标准化疗+帕妥珠单抗组的18.5个月。这相当于中位无进展生存期延长6.1个月、疾病进展或死亡的风险降低38%，具有统计学意义。上述结果发表在《新英格兰医学杂志》上(2012;366:109-19)。

这项双盲Ⅲ期试验招募了808例年龄≥18岁的患者，均确诊为HER2阳性转移或局部复发、无法切除的乳腺癌。将其随机分为两组，分别给予标准化疗(曲妥珠单抗+多西他赛)+安慰剂，或标准化疗+帕妥珠单抗。CLEOPATRA试验的初步数据已于2011年12月上旬在圣安东尼奥乳腺癌研讨会上公布。

供应和费用值得关注

根据基因泰克和FDA宣布帕妥珠单抗获准的声明，生产问题可能会影响该药的长期供应。

该药企全球技术运营部门的主管Patrick Y. Yang博士说：“我们希望能满足患者对帕妥珠单抗的需求。近期我们发现了可能会影响未来该药供应的一个细胞生长问题。我们高度重视这一问题，正在与FDA协作以确保生产流程的稳定，并保证该药能持续供应给需要它的患者。”

在Perjeta获准的同时，基因泰克同意就该药生产流程的相关事项做出承诺，包括接受FDA对接下来几批药品的数据进行审查。

FDA药物评估与研究中心主任Janet Woodcock博士称，只有未曾出现生产问题的药物才可能得到FDA的批准。她在FDA的声明中指出：“鉴于转移性乳腺癌需要额外治疗，我们决定今天批准该药，而不是等到未来供应隐患消除后再予批准，以便使患者更早得以使用该药。基因泰克目前正在制订计划，以缓冲潜在供应短缺问题对患者的影响。”

另一个隐忧是双重HER2抑制的费用问题。根据《纽约时报》的报道，基因泰克打算将帕妥珠单抗的批发价定为5,900美元/月，加上曲妥珠单抗治疗通常需要4,500美元/月，18个月的治疗将花费多达187,000美元。

 

药品标签上印制加框警告

帕妥珠单抗的适应证为，与曲妥珠单抗和多西他赛联用于“未曾应转移接受抗HER2治疗或化疗的HER2阳性转移性乳腺癌患者”。

FDA称，帕妥珠单抗的标签上将会出现一个加框警告，以提醒临床医生和患者警惕胎儿死亡或严重不良反应的潜在风险。“必须在开始Perjeta治疗之前确定妊娠状态，患者应当在开始使用帕妥珠单抗之前被告知这一风险，并采取有效的避孕措施。”

FDA还指出，在联用帕妥珠单抗和曲妥珠单抗+多西他赛的患者中观察到的最常见不良反应包括，腹泻、脱发、中性粒细胞减少、恶心、皮疹和外周感觉神经病。

尽管曾观察到左心室功能障碍，但FDA称，与安慰剂+标准化疗相比，联用帕妥珠单抗和标准化疗“与症状性左心室收缩功能障碍或左心室射血分数下降的发生率增加无关”。

FDA建议，帕妥珠单抗的初始用量为840 mg，60 min内静脉输注，之后每3周给药420 mg，30~60 min内静脉输注。如果联用曲妥珠单抗和帕妥珠单抗，曲妥珠单抗的初始剂量应为8 mg/kg，90 min内静脉输注，之后每3周给药6 mg/kg，30~90 min内静脉输注。如果在使用帕妥珠单抗时合用多西他赛，建议多西他赛的初始剂量为75 mg/m²静脉输注。如果患者耐受良好，多西他赛剂量可逐步增至100 mg/m²，每3周给药1次。爱思唯尔  版权所有

BY KERRI WACHTERElsevier Global Medical NewsBreaking News

Women with HER2-positive metastatic breast cancer have been given a double-edged sword, with the U.S. Food and Drug Administration granting accelerated approval to pertuzumab on Friday, June 8, as a first-line therapy.

The addition of pertuzumab, a new HER2 blocker, to a standard chemotherapy combination of trastuzumab and docetaxel has been shown to extend progression-free survival in these patients. Overall survival data are not yet available.

Pertuzumab is a humanized monoclonal antibody, manufactured through biotechnology methods by Genentech, a subsidiary of Roche. It also blocks other HER family members, including EGFR, HER3, and HER4, and is believed to complement HER2 inhibition by trastuzumab, also made by Genentech and Roche.

The approval rides largely on the results of the CLEOPATRA (Clinical Evaluation of Pertuzumab and Trastuzumab) trial. Dual HER2 blockade boosted median progression-free survival from 12.4 months in a control group treated with only the standard combination to 18.5 months in a group treated with standard therapy plus-pertuzumab. This is a statistically significant difference that corresponds to a 38% reduction in the risk for progression or death and an increase of 6.1 months in median progression-free survival. These results were published in the New England Journal of Medicine (2012;366:109-19).

For the double-blind phase III trial, 808 patients aged 18 years and older with centrally confirmed HER2-positive metastatic or locally recurrent, unresectable breast cancer were randomized either to a control group that received placebo plus trastuzumab and docetaxel or to the pertuzumab group, which received pertuzumab plus trastuzumab and docetaxel.

Preliminary data from the CLEOPATRA trial were presented at the annual San Antonio Breast Cancer Symposium in early December 2011. For expert commentary on the trial, see our video report.

Supply, Cost Could Be Concerns

In their announcements of pertuzumab approval, Genentech, maker of the drug, and the FDA disclosed that production issues could affect the long-term supply of the drug.

“We expect to meet demand for [pertuzumab] following today's FDA approval. We recently identified a cell growth issue that might affect our future supply of the medicine,” said Patrick Y. Yang, Ph.D., head, Pharma Global Technical Operations. “We take this very seriously and are working with the FDA to ensure a consistent manufacturing process that maintains drug supply for the people who need it.”

With the approval, Genentech has agreed to postmarketing commitments related to the manufacturing process for Perjeta. These include FDA review of data from the next several productions of the medicine.

The FDA limited its approval to drug product that has not been affected by production issues, according to Dr. Janet Woodcock, director of FDA’s Center for Drug Evaluation and Research.

“Given the need for additional treatments for metastatic breast cancer, we made the decision to approve this drug today and not to delay its availability to patients pending resolution of the production issues relating to future supply,” she said in the FDA announcement.

“Genentech is currently developing a plan to mitigate the effect on patients of any potential shortage of Perjeta.”

An added concern is the high cost of dual HER2 inhibition at a time when oncologists are under pressure to contain costs. According to the New York Times, Genentech is putting the wholesale cost of pertuzumab at $5,900/month, which added to the typical $4,500/month costs of trastuzumab, would drive the cost of 18 months of treatment to $187,000.

Boxed Warning Put on Label

Pertuzumab is indicated in combination with trastuzumab and docetaxel for “patients with HER2-positive metastatic breast cancer who have not received prior anti–HER2 therapy or chemotherapy for metastatic disease.”

The FDA announced that pertuzumab would have a boxed warning on its label. This is to alert clinicians and patients to the potential risk of death or severe effects to a fetus. “Pregnancy status must be verified prior to the start of Perjeta treatment,” it said; patients should be advised “of these risks and need for effective contraception prior to starting pertuzumab.”

According to the agency, the most common side effects observed with use of pertuzumab in combination with trastuzumab and docetaxel were diarrhea, alopecia, neutropenia, nausea, fatigue, rash, and peripheral sensory neuropathy.

Although left ventricular dysfunction was observed, the FDA said the combination of pertuzumab with standard therapy “was not associated with increases in the incidence of symptomatic left ventricular systolic dysfunction or decreases in left ventricular ejection fraction, compared with placebo in combination with trastuzumab and docetaxel.

The FDA recommended that pertuzumab be started at an initial dose of 840 mg administered as a 60-minute IV infusion, followed every 3 weeks, thereafter, by 420 mg administered as a 30- to 60-minute IV infusion. It also recommended that when trastuzumab is used with pertuzumab, trastuzumab should be started at 8 mg/kg administered as a 90-minute IV infusion, followed every 3 weeks by a dose of 6 mg/kg administered IV over 30 to 90 minutes. When docetaxel is given with pertuzumab, the recommended starting docetaxel dose is 75 mg/m² administered as an IV infusion. If well tolerated, docetaxel may be escalated to 100 mg/m² every 3 weeks.