Ramucirumab被FDA批准用于AFP升高的HCC的二线治疗

StephenW

Ramucirumab Approved by FDA for Second-Line Treatment of AFP-Elevated HCC
Gina Columbus
Published Online:8:22 PM, Fri May 10, 2019

Ramucirumab (Cyramza) monotherapy has received an approval from the FDA for the treatment of patients with hepatocellular carcinoma (HCC) who have an alpha fetoprotein (AFP) of ≥400 ng/ML and have been previously treated with sorafenib (Nexavar).1

The FDA issued its approval based on findings from the international, double-blind, placebo-controlled, multicenter phase III REACH-2 trial, in which the median overall survival (OS) was 8.5 months with ramucirumab compared with 7.3 months with placebo (HR, 0.71; 95% CI, 0.53-0.95, P = .020) in patients who experienced progression on or intolerance to frontline sorafenib.

The results, which were previously presented at the 2018 ASCO Annual Meeting, additionally showed that the survival benefit was consistent across all prespecified subgroups. The 12- and 18-month OS rates both favored ramucirumab at 36.8% versus 30.3% and 24.5% versus 11.3%, respectively. Moreover, the median progression-free survival (PFS) was 2.8 months with ramucirumab compared with 1.6 months with placebo (HR, 0.452; 95% CI, 0.339-0.603; P <.0001).

In the previously reported REACH trial of patients with advanced HCC, treatment with ramucirumab did not significantly improve OS in the intention-to-treat population.2,3 However, a prespecified subgroup analysis revealed a significant survival benefit in patients with AFP levels ≥400 ng/mL. The observation provided a rationale for a follow-up trial to evaluate ramucirumab in patients with HCC associated with elevated AFP.

Eligibility criteria for the REACH-2 trial included a diagnosis of HCC and Barcelona Clinic Liver Cancer (BCLC) stage B or C, Child-Pugh score of A, AFP ≥400 ng/mL, disease progression with first-line sorafenib, and disease refractory to or not amenable to local treatment. In the study, patients were randomized 2:1 to receive ramucirumab intravenously at 8 mg/kg plus best supportive care or placebo/best supportive care every 2 weeks until disease progression or unacceptable toxicity. The primary endpoint was OS; secondary endpoints included PFS, time to progression, response rate, time to symptom deterioration, and safety.

Data analysis included 292 randomized patients (197 to ramucirumab, 95 to placebo) enrolled at centers in North and South America, Europe, Israel, Australia, and Asia (excluding Japan). Patients received best supportive care plus either placebo or ramucirumab (8 mg/kg IV) every 2 weeks.

The patients had a median age of 64, and men accounted for about 80% of the study population. A majority of patients had Child-Pugh score A-5, more than 80% had BCLC stage C, and disease etiology was hepatitis B or C in about two-thirds of cases.

The median follow-up time was 7.9 versus 6.6 months in the experimental and control arms, respectively. The objective response rate showed a numerical advantage for the ramucirumab group (4.6% vs 1.1%; nonsignificant at P = .1697 ). Comparison of disease control rates showed a significant advantage for the ramucirumab arm (59.9% vs 38.9%; P = .0006).

Regarding safety, ramucirumab was associated with more treatment-related adverse events (AEs), but was generally well tolerated. The most commonly reported grade ≥3 AEs in the ramucirumab arm were hypertension (12.2%), ascites (4.1%), and fatigue (3.6%). Zhu reported that 10.7% of patients in the ramucirumab arm discontinued treatment because of AEs, and 3 fatal treatment-related AEs occurred in the group. A third of the patients in the ramucirumab group required dose adjustments to manage treatment-related AEs.

Analysis of AEs of special interest also showed low rates of grade ≥3 events in the ramucirumab arm, including liver injury/failure (18.3%, including ascites), hypertension (12.7%), and bleeding/hemorrhage (5.1%).

In the previously reported data from the randomized phase III REACH study, the median OS in the full, unselected population was 9.2 months with ramucirumab compared with 7.6 months with placebo (HR, 0.87; 95% CI, 0.72-1.05; P = .14). The numerical difference of 1.6 months between the 2 arms did not cross the barrier for statistical significance.

In the planned analysis of patients with HCC and elevated AFP, the median OS for patients with a baseline AFP ≥400 ng/mL was 7.8 months in the ramucirumab arm compared with 4.2 months with placebo (HR, 0.674; 95% CI, 0.51-0.90; P = .0059). In contrast, for patients with a baseline AFP <400 ng/mL, the median OS was 10.1 months with ramucirumab versus 11.8 months with placebo.

StephenW

Ramucirumab被FDA批准用于AFP升高的HCC的二线治疗
吉娜哥伦布
在线发布时间：2019年5月10日星期五晚上8点22分

Ramucirumab（Cyramza）单药治疗已获得FDA批准，用于治疗肝细胞癌（HCC）患者，其甲胎蛋白（AFP）≥400ng/ ML且先前已接受索拉非尼治疗（Nexavar）.1

FDA根据国际，双盲，安慰剂对照，多中心III期REACH-2试验的结果发布了批准，其中ramucirumab的中位总生存期（OS）为8.5个月，而安慰剂为7.3个月（HR）对于前列索拉非尼进展或不耐受的患者，0.71; 95％CI，0.53-0.95，P = .020）。

之前在2018年ASCO年会上发布的结果显示，所有预先指定的亚组的生存获益是一致的。 12个月和18个月的OS率均有利于ramucirumab，分别为30.3％和30.3％，24.5％和11.3％。此外，ramucirumab的中位无进展生存期（PFS）为2.8个月，而安慰剂组为1.6个月（HR，0.452; 95％CI，0.339-0.603; P <.0001）。

在先前报道的晚期HCC患者的REACH试验中，ramucirumab治疗并未显着改善意向治疗人群的OS。 2,3然而，预先指定的亚组分析显示，AFP水平≥400Ng/ mL的患者存活率显着。该观察为后续试验提供了理论依据，以评估与AFP升高相关的HCC患者中的ramucirumab。

REACH-2试验的资格标准包括诊断为HCC和巴塞罗那临床肝癌（BCLC）B期或C期，Child-Pugh评分为A，AFP≥400ng/ mL，疾病进展为一线索拉非尼和疾病难以适应或不适合局部治疗。在该研究中，患者以2：1随机分组接受ramucirumab静脉注射8 mg / kg加上最佳支持治疗或安慰剂/最佳支持治疗，每2周一次，直至疾病进展或不可接受的毒性。终点是OS;次要终点包括PFS，进展时间，反应率，症状恶化时间和安全性。

数据分析包括292名随机患者（197名为ramucirumab，95名为安慰剂），分别在北美和南美，欧洲，以色列，澳大利亚和亚洲（日本除外）的中心就诊。患者每2周接受最好的支持治疗加安慰剂或ramucirumab（8 mg / kg IV）。

患者的中位年龄为64岁，男性约占研究人群的80％。大多数患者的Child-Pugh评分为A-5，超过80％的患者患有BCLC C期，并且在约三分之二的病例中疾病病因为乙型或丙型肝炎。

实验组和对照组的中位随访时间分别为7.9和6.6个月。客观反应率显示ramucirumab组的数值优势（4.6％对1.1％; P = .1697无显着性）。控制率显示ramucirumab组具有显着优势（59.9％对38.9％; P = .0006）。

关于安全性，ramucirumab与更多与治疗相关的不良事件（AEs）相关，但通常耐受性良好。 ramucirumab组最常报告≥3级AE是高血压（12.2％），腹水（4.1％）和疲劳（3.6％）。朱报告，ramucirumab组10.7％的患者因AEs停止治疗，3例发生致命治疗相关的AE。 ramucirumab组中三分之一的患者需要调整剂量以控制治疗相关的AE。

对特别感兴趣的AE的分析还显示ramucirumab组的≥3级事件发生率低，包括肝损伤/衰竭（18.3％，包括腹水），高血压（12.7％）和出血/出血（5.1％）。

在先前报告的随机III期REACH研究数据中，完全未选择人群的中位OS为ramucirumab的9.2个月，而安慰剂为7.6个月（HR，0.87; 95％CI，0.72-1.05; P = .14两组之间1.6个月的数字差异没有跨越障碍具有统计学意义。

在对HCC患者和AFP升高的患者的计划分析中，基线AFP≥400ng/ mL患者的中位OS在ramucirumab组为7.8个月，而安慰剂为4.2个月（HR，0.674; 95％CI，0.51- 0.90; P = .0059）。相比之下，对于基线AFP <400 ng / mL的患者，ramucirumab的中位OS为10.1个月，而安慰剂为11.8个月。