Keytruda批准加速批准治疗HCC

StephenW

NOVEMBER 20, 2018
Keytruda Granted Accelerated Approval for Treatment of HCC

The FDA expanded the approved indications for pembrolizumab (Keytruda, Merck), granting the checkpoint inhibitor accelerated approval for the treatment of patients with hepatocellular carcinoma (HCC) previously treated with sorafenib (Nexavar, Bayer).
"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 Andrew X. Zhu, MD, PhD, the lead investigator of the KEYNOTE-224 trial, on which the approval was based. Dr. Zhu, the director of liver cancer research at Massachusetts General Hospital, in Boston, called the approval “important,” noting “it provides a new treatment option for patients with hepatocellular carcinoma who have been previously treated with sorafenib.”



During the single-arm, multicenter KEYNOTE-224 trial (ClinicalTrials.gov Identifier: NCT02702414), Dr. Zhu and his colleagues evaluated 104 patients with HCC who had disease progression on or after sorafenib or intolerance to sorafenib. The patients were a median age of 68 years (67% aged 65 years or older); 83% were men; 81% were white and 14% were Asian. All patients had measurable disease, ECOG Performance Status of 0 (61%) or 1 (39%), and Child-Pugh class A liver impairment: A5 (72%), A6 (22%), B7 (5%) and B8 (1%). Sixty-four percent of patients had extrahepatic disease, 17% had vascular invasion, and 9% had both; 38% had alfa-fetoprotein levels greater than 400 mcg/mL. Twenty-one percent of the patients enrolled were hepatitis B virus (HBV)-seropositive, 25% were hepatitis C virus (HCV)-seropositive, and nine patients (9%) were seropositive for both HBV and HCV.

Exclusion criteria were active autoimmune disease, more than one etiology of hepatitis, medical conditions requiring immunosuppression, or evidence of ascites.

Patients were given 200 mg of pembrolizumab as an IV infusion every three weeks until disease progression or unacceptable toxicity, for up to 24 months. The median duration of exposure to pembrolizumab was 4.2 months (range, one day to 1.5 years).

The major efficacy outcome measures were objective response rate (ORR) and duration of response according to RECIST (Response Evaluation Criteria in Solid Tumors) version 1.1, 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 (ICR). The confirmed ICR-assessed ORR was 17% (95% CI, 11-26), with one complete response and 17 partial responses. Among the responding patients (n=18), response durations ranged from 3.1 to 16.7 months; 89% of responders had response durations of six months or longer, and 56% had response durations of 12 months or longer.

Adverse events (AEs) occurring in patients with HCC were similar to those described in the pembrolizumab product labeling; however, there were increased incidences of grade 3 or 4 ascites (8%) and immune-mediated hepatitis (2.9%). Grade 3 and 4 laboratory abnormalities that occurred at a higher incidence than in other pembrolizumab trials were elevated aspartate aminotransferase (20%), alanine aminotransferase (9%) and hyperbilirubinemia (10%).

The pembrolizumab prescribing information includes a warning related to immune-mediated AEs, which may be severe or fatal, that can occur with pembrolizumab, including pneumonitis, colitis, hepatitis, endocrinopathies, nephritis, severe skin reactions, solid-organ transplant rejection and complications of allogeneic hematopoietic cell transplantation. Based on the severity of the adverse reaction, pembrolizumab should be withheld or discontinued and corticosteroids administered if appropriate. Pembrolizumab also can cause severe or life-threatening infusion-related reactions. Based on its mechanism of action, pembrolizumab can cause fetal harm when administered to a pregnant woman.

View the full prescribing information for pembrolizumab.

—Clinical Oncology News Staff

Based on press releases from the FDA and Merck.

StephenW

2018年11月20日
Keytruda批准加速批准治疗HCC

FDA扩大了pembrolizumab（Keytruda，Merck）的批准适应症，授予检查点抑制剂加速批准用于治疗先前用索拉非尼（Nexavar，Bayer）治疗的肝细胞癌（HCC）患者。
“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，但对于晚期复发性疾病的治疗选择仍然有限，”Andrew X. Zhu，医学博士，医学博士，首席研究员说。以批准为基础的KEYNOTE-224试验。波士顿马萨诸塞州综合医院肝癌研究主任朱博士称该批准“重要”，并指出“它为肝细胞癌患者提供了一种新的治疗选择”。曾接受过索拉非尼治疗的人。“



在单臂，多中心KEYNOTE-224试验（ClinicalTrials.gov Identifier：NCT02702414）期间，朱博士及其同事评估了104例患有Hora的患者，他们在索拉非尼或索拉非尼之后或索拉非尼不耐受疾病进展。患者的中位年龄为68岁（67岁或65岁以上）; 83％是男性; 81％为白人，14％为亚洲人。所有患者均有可测量的疾病，ECOG表现状态为0（61％）或1（39％），Child-Pugh A级肝功能损害：A5（72％），A6（22％），B7（5％）和B8 （1％）。 64％的患者有肝外疾病，17％有血管侵犯，9％有两者; 38％的甲胎蛋白水平高于400 mcg / mL。入选的患者中有21％是乙型肝炎病毒（HBV） - 阳性，25％是丙型肝炎病毒（HCV） - 阳性，9名患者（9％）是HBV和HCV血清反应阳性。

排除标准是活动性自身免疫疾病，不止一种肝炎病因，需要免疫抑制的医学病症或腹水证据。

每三周给患者施用200mg的pembrolizumab作为静脉输注直至疾病进展或不可接受的毒性，持续长达24个月。接触pembrolizumab的中位持续时间为4.2个月（范围，一天至1.5年）。

根据RECIST（实体肿瘤反应评估标准）1.1版，主要疗效结果指标是客观反应率（ORR）和反应持续时间，修改为遵循最多10个目标病变和每个器官最多5个目标病变，如通过盲法独立中央评估（ICR）评估。确诊的ICR评估的ORR为17％（95％CI，11-26），一个完全反应和17个部分反应。在响应的患者中（n = 18），反应持续时间为3.1至16.7个月; 89％的响应者的响应持续时间为6个月或更长，56％的响应持续时间为12个月或更长。

HCC患者发生的不良事件（AEs）与pembrolizumab产品标签中描述的相似;然而，3级或4级腹水（8％）和免疫介导性肝炎（2.9％）的发病率增加。发生率高于其他pembrolizumab试验的3级和4级实验室异常的天冬氨酸氨基转移酶（20％），丙氨酸氨基转移酶（9％）和高胆红素血症（10％）升高。

pembrolizumab处方信息包括与pembrolizumab可能发生的免疫介导的AE相关的警告，其可能是严重的或致命的，包括肺炎，结肠炎，肝炎，内分泌病，肾炎，严重的皮肤反应，固体器官移植排斥和并发症。异基因造血细胞移植。根据不良反应的严重程度，应停用或停用pembrolizumab，并在适当时给予皮质类固醇。 Pembrolizumab也可引起严重或危及生命的输液相关反应。根据其作用机制，pembrolizumab在给孕妇服用时会引起胎儿伤害。

查看pembrolizumab的完整处方信息。

- 临床肿瘤新闻工作人员

基于FDA和默克的新闻稿。