FDA批准默克公司的KEYTRUDA®（pembrolizumab）治疗曾接受索拉非尼

StephenW

FDA Approves Merck’s KEYTRUDA® (pembrolizumab) for the Treatment of Patients with Hepatocellular Carcinoma (HCC) Who Have Been Previously Treated with Sorafenib

Approval Marks 14 th Indication for KEYTRUDA
Friday, November 9, 2018 4:21 pm EST  

KENILWORTH, N.J.--(BUSINESS WIRE)--Merck (NYSE:MRK), known as MSD outside the United States and Canada, today announced that the U.S. Food and Drug Administration (FDA) has approved KEYTRUDA, Merck’s anti-PD-1 therapy, for the treatment of patients with hepatocellular carcinoma (HCC) who have been previously treated with sorafenib. This indication is approved under accelerated approval based on tumor response rate and durability of response. Continued approval for this indication may be contingent upon verification and description of clinical benefit in the confirmatory trials.

“Hepatocellular carcinoma is the most common type of liver cancer in adults, and while we have seen recent therapeutic advancements, there are still limited treatment options for advanced recurrent disease,” said Dr. Andrew X. Zhu, lead investigator and director of liver cancer research at Massachusetts General Hospital and professor of medicine at Harvard Medical School. “Today’s approval of KEYTRUDA is important, as it provides a new treatment option for patients with hepatocellular carcinoma who have been previously treated with sorafenib.”

Immune-mediated adverse reactions, which may be severe or fatal, can occur with KEYTRUDA, including pneumonitis, colitis, hepatitis, endocrinopathies, nephritis, severe skin reactions, solid organ transplant rejection, and complications of allogeneic hematopoietic stem cell transplantation (HSCT). Based on the severity of the adverse reaction, KEYTRUDA should be withheld or discontinued and corticosteroids administered if appropriate. KEYTRUDA can also cause severe or life-threatening infusion-related reactions. Based on its mechanism of action, KEYTRUDA can cause fetal harm when administered to a pregnant woman. For more information, see “Selected Important Safety Information” below.

“The approval of KEYTRUDA for advanced hepatocellular carcinoma marks the second FDA approval for hepatocellular carcinoma in Merck’s oncology portfolio this year, underscoring our commitment to help bring forward new treatment options for cancers that have historically been very challenging to treat,” said Dr. Scot Ebbinghaus, vice president, clinical research, Merck Research Laboratories. “We look forward to continuing to advance research for hepatocellular carcinoma across our portfolio with the goal to help even more patients affected by this type of cancer.”

Data Supporting the Approval

The approval was based on data from KEYNOTE-224, a single-arm, open-label, multicenter trial evaluating KEYTRUDA in 104 patients with HCC who had disease progression on or after sorafenib or were intolerant to sorafenib. Additional eligibility included having measurable disease and Child-Pugh class A liver impairment. Patients with active and inactive hepatitis B virus (HBV) as well as patients with past or ongoing hepatitis C virus (HCV) infection were eligible for the trial. Patients with active autoimmune disease, greater than one etiology of hepatitis, a medical condition that required immunosuppression, or clinical evidence of ascites by physical exam were ineligible for the trial.

Patients received KEYTRUDA 200 mg every three weeks until unacceptable toxicity or confirmed disease progression. Patients without disease progression were treated for up to 24 months. Assessment of tumor status was performed every nine weeks. The major efficacy outcome measures were objective response rate (ORR) and duration of response according to RECIST v1.1, modified to follow a maximum of 10 target lesions and a maximum of five target lesions per organ, as assessed by blinded independent central review (BICR).

Among the 104 patients treated, the baseline characteristics were: median age 68 years (67% age 65 or older); 83 percent were male; 81 percent were White; 14 percent were Asian; ECOG PS of 0 (61%) or 1 (39%); Child Pugh class and score were A5 (72%), A6 (22%), B7 (5%), and B8 (1%); 21 percent were HBV seropositive and 25% HCV seropositive. Nine patients (9%) were seropositive for both HBV and HCV. Sixty-four percent of patients had extrahepatic disease, 17 percent had vascular invasion, and 9 percent had both, and 38 percent had alfa-fetoprotein (AFP) levels greater than 400 ug/mL. All patients received prior sorafenib; reasons for discontinuation were intolerance in 20 percent of patients.

In KEYNOTE-224, the ORR was 17 percent (95% CI, 11-26), with a complete response rate of 1 percent and a partial response rate of 16 percent. Among the responding patients (n=18), 89 percent experienced a DOR for six months or longer and 56 percent experienced a DOR for 12 months or longer.

Among the 104 patients in KEYNOTE-224, the median duration of exposure to KEYTRUDA was 4.2 months (range, 1 day to 1.5 years). Adverse reactions occurring in patients with HCC were generally similar to those in patients with melanoma or non-small cell lung cancer, with the exception of increased incidences of ascites (8% Grades 3-4) and immune-mediated hepatitis (2.9%). Laboratory abnormalities (Grades 3-4) that occurred at a higher incidence were elevated AST (20%), ALT (9%), and hyperbilirubinemia (10%).

StephenW

FDA批准默克公司的KEYTRUDA®（pembrolizumab）治疗曾接受索拉非尼治疗的肝细胞癌（HCC）患者

Approval标志着KEYTRUDA的第14次指示
美国东部时间2018年11月9日星期五下午4:21

美国新泽西州肯尼沃市 - （美国商业资讯） - Merck（纽约证券交易所股票代码：MRK），在美国和加拿大之外被称为MSD，今天宣布美国食品和药物管理局（FDA）批准了KEYTRUDA，默克公司的抗PD-1治疗，用于治疗先前曾接受过索拉非尼治疗的肝细胞癌（HCC）患者。该指征基于肿瘤反应率和反应持久性在加速批准下获得批准。对该指征的持续批准可能取决于确认试验中的临床益处的验证和描述。

“肝细胞癌是成人中最常见的肝癌类型，虽然我们已经看到最近的治疗进展，但对晚期复发性疾病的治疗选择仍然有限，”首席研究员兼肝癌主任Andrew X. Zhu博士说。马萨诸塞州综合医院的研究和哈佛医学院的医学教授。 “今天对KEYTRUDA的认可非常重要，因为它为以前接受过索拉非尼治疗的肝细胞癌患者提供了一种新的治疗方案。”

KEYTRUDA可能发生免疫介导的不良反应，可能是严重的或致命的，包括肺炎，结肠炎，肝炎，内分泌疾病，肾炎，严重的皮肤反应，实体器官移植排斥和同种异体造血干细胞移植（HSCT）的并发症。根据不良反应的严重程度，应禁止或停用KEYTRUDA，并在适当时给予皮质类固醇。 KEYTRUDA还可能导致严重或危及生命的输液相关反应。根据其作用机制，KEYTRUDA在给孕妇服用时会造成胎儿伤害。有关详细信息，请参阅下面的“所选重要安全信息”。

“KEYTRUDA对晚期肝细胞癌的批准标志着今年FDA批准了Merck肿瘤组合中肝细胞癌的第二次批准，强调了我们的承诺，即为历史上非常具有挑战性的癌症提供新的治疗选择，”Scot博士说。默克研究实验室临床研究副总裁艾宾浩斯。 “我们期待在我们的产品组合中继续推进肝细胞癌的研究，目标是帮助更多受此类癌症影响的患者。”

支持批准的数据

该批准是基于KEYNOTE-224的数据，KEYNOTE-224是一项单臂，开放标签，多中心试验，评估了104例HCC患者的KEYTRUDA，这些患者在索拉非尼或索拉非尼治疗后出现疾病进展或对索拉非尼不耐受。其他资格包括可测量疾病和Child-Pugh A级肝功能损害。患有活动性和非活动性乙型肝炎病毒（HBV）的患者以及患有过去或正在进行的丙型肝炎病毒（HCV）感染的患者均有资格进行试验。患有活动性自身免疫疾病，多于一种肝炎病因，需要免疫抑制的医学病症或通过体检的腹水临床证据的患者不适合进行该试验。

患者每三周接受KEYTRUDA 200mg，直至出现不可接受的毒性或确诊的疾病进展。没有疾病进展的患者治疗长达24个月。每九周进行一次肿瘤状态评估。主要疗效结果指标是根据RECIST v1.1的客观反应率（ORR）和反应持续时间，经过修改，最多可追踪10个目标病灶，每个器官最多有5个靶病变，通过盲法独立中心评估（ BICR）。

在104名接受治疗的患者中，基线特征为：中位年龄68岁（67岁或65岁以上）; 83％是男性; 81％是白人;亚洲人占14％; ECOG PS为0（61％）或1（39％）; Child Pugh分级和分数分别为A5（72％），A6（22％），B7（5％）和B8（1％）; 21％为HBV血清阳性，25％为HCV血清反应阳性。 9名患者（9％）对HBV和HCV均呈血清反应阳性。 64％的患者患有肝外疾病，17％的患者有血管侵犯，9％的患者同时患有血管，38％的患者的甲胎蛋白（AFP）水平高于400 ug / mL。所有患者均接受索拉非尼治疗;停止的原因是20％的患者不耐受。

在KEYNOTE-224中，ORR为17％（95％CI，11-26），完全响应率为1％，部分响应率为16％。在响应的患者中（n = 18），89％的患者在6个月或更长时间内接受DOR治疗，56％的患者在12个月或更长时间内接受DOR治疗。
在KEYNOTE-224的104名患者中，KEYTRUDA暴露的中位持续时间为4.2个月（范围，1天至1。5年）。 HCC患者发生的不良反应与黑色素瘤或非小细胞肺癌患者的不良反应基本相似，但腹水（8％3-4级）和免疫介导性肝炎（2.9％）发生率增加除外。 发生率较高的实验室异常（3-4级）发生AST升高（20％），ALT升高（9％）和高胆红素血症（10％）。