Cabozantinib在肝癌发生中的三期结果

StephenW

Phase 3 Results of Cabozantinib in Hepatocellular Carcinoma Released
JANUARY 17, 2018
Mathew Shanley
This morning, Ipsen and Exelixis, Inc. announced detailed results of the pivotal phase 3 CELESTIAL trial, evaluating cabozatinib in previously treated patients with advanced hepatocellular carcinoma (HCC).

The data will be presented in a late-breaking oral session at the 2018 American Society of Clinical Oncology (ASCO) GI Symposium being held in San Francisco this weekend.

HCC, the world’s third-leading cause of death due to cancer, affects less than 200,000 people in the United States, and is has a generally poor prognosis with 5-year survival rates ranging from 3% for advanced cancer to 31% for localized forms. It is often the result of a chronic hepatitis B infection, and is a primary malignancy of the liver that occurs mostly in patients with chronic liver disease and cirrhosis.

Presentation of it most frequently transpires in later stages with right-upper-quadrant pain, weight loss, and signs of decompensated liver disease.

Cabozantinib is a small molecule inhibitor of receptors, including VEGFR, MET and AXL, being developed to be administered orally. In preclinical models, it has been shown to inhibit the activity of these receptors, which are involved in normal cellular function and pathologic processes like tumor angiogenesis, invasiveness, metastasis and drug resistance.

By September 2017, the trial had enrolled 760 patients with advanced HCC who received prior sorafenib and may have received up to 2 prior systemic cancer therapies for HCC and had adequate liver function.

Results from the CELESTIAL study showed cabozantinib’s ability to provide a statistically significant and clinically meaningful improvement in overall survival (OS), the trial’s primary endpoint, when compared to placebo at the planned second interim analysis for the population of second- and third-line patients enrolled in this study. Median OS was 10.2 months in patients administered cabozantinib versus 8.0 months in those given placebo.

Additionally, median progression-free survival (PFS) was more than doubled, at 5.2 months with cabozantinib and 1.9 months with placebo. Disease control (partial response or stable disease) was achieved by 64% of the cabozantinib group compared with 33% of the placebo group.

Ghassan K. Abou-Alfa, M.D., Memorial Sloan Kettering Cancer Center, New York and lead investigator on CELESTIAL stresses the impact the drug could have if approved: “Patients with advanced hepatocellular carcinoma often have a poor prognosis and limited treatment options following prior systemic therapy,” he said. “The clinically significant benefits in both overall survival and progression-free survival shown in the CELESTIAL trial suggest that, if approved, cabozantinib could become an important addition to the treatment landscape for these patients.”

Dr Abou-Alfa will present the data during Oral Abstract B: Cancers of the Pancreas, Small Bowel, and Hepatobiliary Tract on Friday afternoon. Exelixis and Ipsen intend to submit a supplemental New Drug Application (NDA) to the U.S. Food and Drug Administration (FDA) in the first quarter of 2018.

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StephenW

Cabozantinib在肝癌发生中的三期结果
2018年1月17日
Mathew Shanley
今天上午，Ipsen和Exelixis公司宣布了关键阶段3 CELESTIAL试验的详细结果，评估了先前接受治疗的晚期肝细胞癌（HCC）患者的卡扎他尼。

数据将在本周末在旧金山举行的2018年美国临床肿瘤学会（ASCO）GI研讨会上进行最后一次口头报告。

HCC是世界上第三大癌症致死原因，影响到美国不到20万人，预后普遍较差，5年生存率从晚期癌症的3％到局部形态的31％ 。它通常是慢性乙型肝炎感染的结果，并且是主要在慢性肝病和肝硬化患者中发生的肝脏原发性恶性肿瘤。

最常见的表现是右上腹疼痛，体重减轻和失代偿肝脏疾病的后期。

Cabozantinib是受体的小分子抑制剂，包括VEGFR，MET和AXL，被开发用于口服给药。在临床前模型中，已显示抑制这些受体的活性，这些受体涉及正常的细胞功能和肿瘤血管生成，侵袭性，转移和耐药性等病理过程。

到2017年9月，该试验招募了760例先前接受索拉非尼的晚期HCC患者，可能已经接受了2次以前用于HCC的系统性癌症治疗，并具有足够的肝功能。

来自CELESTIAL研究的结果显示，在计划的第二和第三线患者的第二次中期分析中，与安慰剂相比，cabozantinib能够提供统计学显着的和临床上有意义的总体生存（OS）改善，试验的主要终点参加这项研究。接受卡唑替尼治疗的患者的中位OS为10.2个月，安慰剂组为8.0个月。

此外，中位无进展生存期（PFS）增加了一倍以上，卡唑替尼组为5.2个月，安慰剂组为1.9个月。卡唑替尼组为64％，而安慰剂组为33％，疾病控制（部分缓解或稳定疾病）达到了64％。

纽约Memorial Sloan Kettering癌症中心的Ghassan K. Abou-Alfa博士和CELESTIAL的首席研究员强调，如果获得批准，药物可能具有的影响：“患有晚期肝细胞癌的患者往往预后不良，而且以前的系统治疗选择有限治疗，“他说。 CELESTIAL试验显示，临床上显着的总生存期和无进展生存期益处表明，如果获得批准，cabozantinib可能成为这些患者治疗情况的重要补充。

Abou-Alfa博士将在星期五下午的口腔摘要B：胰腺癌，小肠癌和肝胆道肿瘤期间提供数据。 Exelixis和Ipsen计划在2018年第一季度向美国食品和药物管理局（FDA）提交补充新药申请（NDA）。

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