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首页 » 癌症研究 » ESMO2016:肝癌治疗重大突破!Regorafenib显著提高肝细胞癌患者的寿命

ESMO2016:肝癌治疗重大突破!Regorafenib显著提高肝细胞癌患者的寿命

来源:生物谷 2016-07-01 19:17

2016年7月1日/生物谷BIOON/--根据欧洲临床肿瘤学会(ESMO)在西班牙巴塞罗纳市举行的第18届世界胃肠道癌症大会发布的III期RESORCE临床试验的数据,相比于安慰剂,口服多激酶抑制剂瑞格非尼(regorafenib)显著地改善肝细胞癌(HCC)患者的存活率。

这项临床研究的主要研究员、巴塞罗纳大学医院门诊部BCLC小组负责人Jordi Bruix博士说,“长期以来,人们利用单个试剂索拉非尼(sorafenib)对肝细胞癌进行系统治疗。在将近10年前,就已证实这种药物能够显著提高预期寿命。在此之前,还没有其他试剂在疗效上能够超过它。”

尽管过去十年,人们发现很多能够潜在治疗肝细胞癌的新试剂在临床试验中失败了,但是来自早前的瑞格非尼临床试验的I期和II期数据导致来自中国、西班牙、法国、意大利、匈牙利、日本、俄罗斯、英国和德国的研究人员启动这项国际性的多中心III期临床试验。

研究人员招募了573名之前接受过索拉非尼治疗的中晚期肝细胞癌患者,按照2:1的比例对他们进行随机分配,在每4周时间的1至3周内每天服用160mg瑞格非尼或者安慰剂,除此之外,他们都接受最好的支持性护理。

在接受平均3.6个月的治疗后,相比于服用安慰剂的患者,服用瑞格非尼的患者死亡风险下降了38%,病情恶化风险下降了54%。

对服用瑞格非尼的患者而言,平均无进展存活期(mean progression-free survival, 也译作平均无进展生存期)是3.1个月,而对服用安慰剂的患者而言, 这一数字是1.5个月。对服用瑞格非尼的患者而言,整体存活期中位数(median overall survival)是10.6个月,而对服用安慰剂的患者而言, 这一数字是7.8个月。

总地来说,65.2%服用瑞格非尼的患者表现出病情完全缓解、部分缓解或稳定,相比对之下,对服用安慰剂的患者而言,这一数字是36.1%。

瑞格非尼具有与索拉非尼相类似的安全性和副作用,其中服用瑞格非尼的患者产生的更加常见的副作用是高血压、手足皮肤反应、疲劳和腹泻。

Bruix博士说,这种药物的疗效与肝细胞癌的病因或分期无关,但是对这种癌症的生物标志物进行分析有助于揭示出某一部分患者可能更受益于这种药物的治疗。

Bruix博士说,“治疗肝细胞癌是非常困难的,但是如今我们有一种有效的二线试剂,这对肝细胞癌患者而言是个好消息,对促进这个领域的人们有兴趣进一步开发而言也是个好消息。”(生物谷 Bioon.com)

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Efficacy and safety of regorafenib versus placebo in patients with hepatocellular carcinoma (HCC) progressing on sorafenib: Results of the international, randomized phase 3 RESORCE trial

Jordi Bruix1, Philippe Merle2, Alessandro Granito3, Yi-Hsiang Huang4, Gyorgy Bodoky5, Osamu Yokosuka6, Olivier Rosmorduc7, Valeriy Breder8, Rene Gerolami9, Gianluca Masi10, Paul J Ross11, Shukui Qin12, Tianqiang Song13, Jean-Pierre Bronowicki14, Isabelle Ollivier-Hourmand15, Masatoshi Kudo16, Marie-Aude LeBerre17, Annette Baumhauer18, Gerold Meinhardt19, Guohong Han20, on behalf of the RESORCE Investigators

Background: There are no proven or approved second-line treatment options for patients with advanced HCC. Based on promising activity in a second-line phase 2 study (Bruix, Eur J Cancer 2013), we evaluated regorafenib, an oral multikinase inhibitor, in patients with intermediate or advanced HCC who had disease progression on sorafenib.

Methods: In this double-blind, placebo-controlled trial, adults with HCC Barcelona Clinic Liver Cancer (BCLC) stage B or C who received sorafenib for ≥20 days at ≥400 mg/day and had documented radiological progression on sorafenib, Child-Pugh A liver function, and ECOG performance status 0-1 were randomized 2:1 (stratification by geographic region Asia vs rest of the world, performance status, alpha-fetoprotein, extrahepatic spread, macroscopic vascular invasion) to regorafenib 160 mg or placebo once daily during weeks 1–3 of each 4-week cycle. All received best supportive care. Treatment continued until disease progression, death, or unacceptable toxicity. The primary endpoint of overall survival (OS) was analyzed by intent-to-treat. Secondary endpoints were progression-free survival (PFS), time-to-progression (TTP), response rate (RR), and disease control rate (DCR).

Results: The trial was conducted in 21 countries and a total of 573 patients were randomized (regorafenib=379; placebo=194). Baseline demographic and disease characteristics were balanced between arms. For all patients, median age was 63 years, 88% were male, and 87% were BCLC stage C. Median (range) treatment duration was 3.6 months (0.03‒29.4) for regorafenib and 1.9 months (0.2‒27.4) for placebo. The regorafenib group had a 38% reduction in the risk of death (HR 0.62; 95%CI 0.50‒0.78; p <0.001); median OS (regorafenib vs placebo) was 10.6 vs 7.8 months. There was a 54% reduction in the risk of progression or death with regorafenib (HR 0.46; 95%CI 0.37‒0.56; p <0.001); median PFS (regorafenib vs placebo) was 3.1 vs 1.5 months. Median TTP (regorafenib vs placebo) was 3.2 vs 1.5 months (HR 0.44; 95%CI 0.36–0.55; p<0.001). DCR (complete and partial responses + stable disease by mRECIST) for regorafenib vs placebo was 65.2% vs 36.1% (p<0.001). Overall RRs (complete and partial responses) were 10.6% vs 4.1% (p=0.005), respectively. Rates of grade ≥3 adverse events were 79.7% with regorafenib and 58.5% with placebo. Most common grade ≥3 adverse events occurring more frequently in the regorafenib group included (regorafenib vs placebo) hypertension (15.2% vs 4.7%), hand-foot skin reaction (12.6% vs 0.5%), fatigue (9.1% vs 4.7%), and diarrhea (3.2% vs 0%). Rates of dose modifications due to adverse events were 68.2% with regorafenib and 31.1% with placebo. Deaths occurring up to 30 days after last dose of study drug were higher in the placebo group (13.4% regorafenib, 19.7% placebo).

Conclusions: Regorafenib significantly improved OS in patients with HCC who progressed during treatment with sorafenib. Adverse events were consistent with the known safety profile of regorafenib.

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