卡本地尼可能是肝癌治疗的新选择

StephenW

Cabozantinib May Be 'New Treatment Option' for Liver Cancer

Roxanne Nelson, RN, BSN

January 24, 2018

SAN FRANCISCO — Treatment with cabozantinib (Cabometyx, Exelixis) significantly improved outcomes in patients with advanced hepatocellular carcinoma (HCC), leading researchers to suggest that it could offer a new treatment option for this patient population.

The new findings come from the phase 3 CELESTIAL trial and were presented at the Gastrointestinal Cancers Symposium (GICS) 2018.

This trial involved 707 patients with HCC who had experienced disease progression with sorafenib (Nexavar, Bayer) or other systemic therapies.

Median overall survival was 2.2 months longer for patients who received cabozantinib as compared to patients who received placebo. The study also met its secondary endpoint of progression-free survival — there was a 56% reduction in the risk for progression or death among patients who received active therapy.

"Cabozantinib represents a new treatment option for patients with advanced HCC after prior systemic anticancer therapy," said lead author Ghassan K. Abou-Alfa, MD, of Memorial Sloan Kettering Cancer Center in New York City.

"It significantly improves overall survival in advanced HCC patients," he said. "Progression-free survival and objective response rate were also significantly improved."

Cabozantinib is an oral inhibitor of multiple receptor tyrosine kinases, including RET, MET, and vascular endothelial growth factor 2 (VEGFR2), which are all involved in both normal cellular function and pathologic processes, such as oncogenesis, metastasis, tumor angiogenesis, and maintenance of the tumor microenvironment.

The drug has been marketed in the United States since 2012, when it was approved for use in the treatment of metastatic medullary thyroid cancer. In 2016, it was also approved for use in advanced renal cell carcinoma in patients who have received previous antiangiogenic therapy.
Details of the Study

Dr Abou-Alfa noted that cabozantinib showed preliminary clinical activity in patients with advanced HCC in a phase 2 trial (Ann Oncol. 2017;28:528-534). In that study, the median progression-free survival was 5.2 months, and the median overall survival was 11.5 months among patients who received cabozantinib.

The phase 3 trial now being reported was conducted in 707 HCC patients who were stratified according to disease etiology (hepatitis B, 38%; hepatitis C, 22%), geographic region (Asia, 25%), and the presence of extrahepatic spread (79%) and/or macrovascular invasion (27%).

The trial allowed for all patients to have previously received up to two lines of systemic therapy for HCC, one of which had to have been sorafenib. Dr Abou-Alfa explained that 100% of patients received sorafenib, owing to the fact that no other drugs had been approved at the time this trial was initiated.

Patients were randomly assigned in a 2:1 ratio to receive 60 mg of cabozantinib orally once daily or placebo. Treatment was continued until loss of clinical benefit or intolerable toxicity. No crossover was permitted.
The study met the primary endpoint at the second planned interim analysis. Results showed that the median overall survival was 10.2 months with cabozantinib vs 8.0 months with placebo; this extrapolated to a 24% reduction in the risk for death (hazard ratio [HR], 0.76; P = .0049).

Progression-free survival was also superior with cabozantinib in comparison with placebo (median: 5.2 months vs 1.9 months; HR, 0.44; P < .0001).

The overall response rate was limited, explained Dr Abou-Alfa; there was a 4% response in the cabozantinib group compared with a 0.4% response with placebo (P = .0086).

There was no complete response in either group. A partial response was seen in 4% of the cabozantinib group and in 0.4% of the placebo group; stable disease occurred in 60% with cabozanitnib vs 33% with placebo; and disease progression occurred in 21% with cabozantinib vs 55% with placebo. In addition, 15% of patients who received cabozantinib and 11% of patients who received placebo were not evaluable.

When stable disease was included, the disease control rate was 64% with cabozantinib vs with 33% with placebo.

In an analysis restricted to patients who had received only sorafenib prior to the study, the median overall survival was higher, at 11.3 months with cabozantinib vs 7.2 months with placebo (HR, 0.70). A small improvement was also seen for progression-free survival (5.5 months vs 1.9 months; HR, 0.40).

After the study, 25% of patients in the cabozantinib arm received subsequent therapy, compared to 30% who received placebo. "Understandably, more patients on placebo went on to other therapies because of early progression," Dr Abou-Alfa said.

The median time to subsequent systemic therapy was 6.6 months for the cabozantinib arm vs 3.3 months for patients who received placebo.

No new safety signals were observed with cabozantinib in this study. The most common grade 3/4 adverse events that occurred with higher frequency in the cabozantinib arm included hand-foot skin reaction (17% vs 0%), hypertension (16% vs 2%), increased aspartate aminotransferase (12% vs 7%), fatigue (10% vs 4%), diarrhea (10% vs 2%), asthenia (7% vs. 2%), and decreased appetite (6% vs <1%).
Problem With Drug Interruption?

In a discussion of the paper, Jordi Bruix, MD, PhD, of the University of Barcelona, in Spain, explained that the study results demonstrate that cabozantinib provides a clinically meaningful survival benefit to patients with advanced HCC who have received previous therapy.

"An important aspect of the trial is that survival in the placebo arm is consistent with findings from other second-line trials with other therapies," Dr Bruix said, "and that is about 8 months."

That is now a benchmark of survival that can be expected without treatment and that can be used in future trials, he pointed out.

One point of concern was that the time to progression with cabozantinib was 3.8 months, whereas the median progression-free survival was 5.5 months. Thus, he wondered whether treatment was interrupted for many of the patients.

"This is something that I would like to see better explored when talking about adverse events and management, to understand to what extent the drug is safe and can be managed," Dr. Bruix said.

He also noted that almost all of the new systemic therapies that have been approved for treatment of advanced HCC target the VEGF pathway. "So this leaves a proportion of patients who cannot benefit and are in need of treatment, and we need to look beyond VEGF," Dr Bruix said. "They are still in need of effective treatment."

Dr Abou-Alfa has participated in a consulting or advisory role with numerous pharmaceutical companies and has received travel expenses from Polaris. Dr Bruix has relationships with Argule, Bayer Schering, BristolMeyersSquibb, Kowa, Novartis, Onexo, Roche, BTG, and Sirtex Medical.

2018 Gastrointestinal Cancers Symposium. Abstract 207, presented January 19, 2018.

StephenW

卡本地尼可能是肝癌治疗的新选择

Roxanne Nelson，RN，BSN

2018年1月24日

0评论
添加到电子邮件提醒

（Cabometyx，Exelixis）治疗显着改善晚期肝细胞癌（HCC）患者的预后，这使得研究人员建议可以为该患者提供新的治疗选择。

新发现来自3期CELESTIAL试验，并在2018年胃肠道癌症研讨会（GICS）上发表。

这项试验涉及707名患有索拉非尼（多吉美，拜耳）疾病进展的HCC患者或其他全身性治疗。

与接受安慰剂的患者相比，接受cabozantinib治疗的患者总生存期中位时间延长了2.2个月。该研究还达到了无进展生存期的第二个终点 - 接受积极治疗的患者的进展或死亡风险降低了56％。

第一作者，纽约纪念斯隆凯特琳癌症中心的医学博士Ghassan K. Abou-Alfa表示：“Cabozantinib代表了先前系统性抗癌治疗后晚期HCC患者的一种新的治疗选择。

他表示：“这大大提高了晚期HCC患者的总生存期。 “无进展生存率和客观缓解率也显着提高。”

Cabozantinib是多种受体酪氨酸激酶（包括RET，MET和血管内皮生长因子2（VEGFR2））的口服抑制剂，均参与正常细胞功能和肿瘤发生，转移，肿瘤血管生成和维持等病理过程的肿瘤微环境。

该药自2012年起在美国上市，当时它被批准用于治疗转移性甲状腺髓样癌。在2016年，它也被批准用于先前接受过抗血管生成治疗的患者的晚期肾细胞癌。
研究细节

Abou-Alfa博士指出，cabozantinib在2期临床试验中显示晚期HCC患者的临床初步活性（Ann Oncol。2017; 28：528-534）。在该研究中，中位无进展生存期为5.2个月，接受卡唑替尼治疗的患者中位总生存期为11.5个月。

目前报道的3期临床试验是在707例根据疾病病因分层的HCC患者中进行的（乙型肝炎，38％;丙型肝炎，22％），地理区域（亚洲，25％）和肝外扩散79 ％）和/或大血管侵犯（27％）。

该试验允许所有患者先前接受多达两行HCC全身治疗，其中之一必须是索拉非尼。 Abou-Alfa博士解释说，100％的患者接受索拉非尼治疗，因为在这个试验开始时没有其他药物被批准。

患者被随机分配到2：1的比例，每天一次或安慰剂口服60mg卡唑替尼。继续治疗直至丧失临床益处或难以忍受的毒性。不允许交叉。
该研究在第二次计划的中期分析中达到了主要终点。结果显示，卡唑替尼组中位总生存期为10.2个月，安慰剂组为8.0个月;这推断死亡风险降低24％（风险比[HR]，0.76; P = 0.0049）。

与安慰剂相比，cabozantinib的无进展生存率也优于中位数（中位数：5.2个月vs1.9个月; HR = 0.44; P <0.0001）。

Abou-Alfa博士解释说，整体回应率有限。 cabozantinib组的反应率为4％，安慰剂组为0.4％（P = 0.0086）。

两组都没有完全的反应。卡唑替尼组有4％有部分反应，安慰剂组有0.4％卡比他尼60％发生稳定性疾病，安慰剂发生率33％;和卡唑替尼组为55％，安慰剂组为55％。此外，接受卡诺替尼治疗的患者中有15％，接受安慰剂治疗的患者中有11％未被评估。

包括稳定的疾病时，卡唑替尼组的疾病控制率为64％，安慰剂组为33％。

总体生存中位数较高，卡唑替尼组为11.3个月，安慰剂组为7.2个月（HR为0.70）。无进展生存率也有一点改善（5.5个月vs 1.9个月; HR，0.40）。

研究结果显示，cabozantinib组25％的患者接受了随后的治疗，而安慰剂组为30％。 Abou-Alfa博士说：“可以理解的是，更多的安慰剂患者因为早期进展而接受其他治疗。

随后的全身治疗的中位时间为cabozantinib组为6.6个月，接受安慰剂的患者为3.3个月。

在这项研究中没有观察到新的安全性信号与cabozantinib。 Cabozantinib组出现频率最高的3/4级不良事件包括手足皮肤反应（17％vs 0％），高血压（16％比2％，天冬氨酸转氨酶升高（12％比7％）， ，疲劳（10％vs 4％），腹泻（10％vs 2％），虚弱（7％vs. 2％），食欲下降1％。
药物中断问题？

西班牙巴塞罗那大学医学博士Jordi Bruix在文章的讨论中解释说，研究结果表明，cabozantinib对接受了既往治疗的晚期HCC患者具有临床意义的生存益处。

Bruix博士说：“试验的一个重要方面是安慰剂组的存活率与其他二线治疗方案与其他治疗方案的结果是一致的，Bruix博士说，”这是大约8个月的时间。

他指出，现在这是一个没有治疗就可以预期的生存基准，可以在未来的试验中使用。

有一点值得关注的是用卡唑替尼治疗的时间为3.8个月，中位无进展生存期为5.5个月。因此，他想知道许多患者的治疗是否中断。

布鲁克斯博士说：“在讨论不良事件和管理时，我希望能够更好地探讨这个问题，了解药物在多大程度上是安全的，可以进行管理。

他还指出，几乎所有已被批准用于晚期HCC治疗的新的全身性治疗靶向VEGF途径。 “因此，这使得一部分患者无法获益，需要治疗，我们需要超越VEGF”Bruix博士说，“他们仍然需要有效的治疗。

Abou-Alfa博士参与了一系列药物的咨询或咨询工作，并已收到北极星的差旅费。 Bruix博士与Argule，Bayer Schering，Bristol Meyers Squibb，Kowa，Novartis，Onexo，Roche，BTG和Sirtex Medical有合作关系。

2018年胃肠癌研讨会。摘要207，呈现于2018年1月19日。