读医学网

据7月2日发表在《美国医学会杂志》上的一则研究披露，尽管有着强有力的临床前数据，但与安慰剂相比，药物依维莫司未能在患晚期肝癌的病人中提高总生存率。

晚期肝细胞性肝癌（HCC;这是肝癌中的一个类型）患者的总体存活中位数不到一年，这在很大程度上是因为没有有效的治疗方法。药物索拉非尼是唯一的显示能在晚期HCC病人中改善总体存活率的系统性治疗药物。根据文章的背景资料，在临床前模型中，依维莫司可阻止肿瘤进展并提高存活率。

波士顿市哈佛医学院马萨诸塞州总医院癌症中心的Andrew X. Zhu, M.D., Ph.D.及其同事将546名晚期HCC成年患者随机性地分派接受依维莫司（n = 362）或安慰剂（n = 184）；这些病人的HCC在使用索拉非尼期间或之后仍然在进展或他们对索拉非尼治疗不耐受；这两组病人都结合使用了最佳的支持性治疗，并一直持续到疾病进展或对毒性变得无法耐受。来自17个国家的病人是在2010年5月至2012年3月间加入这项第三期的研究中的。

研究人员发现这2组间在总体存活率上没有显著的差异：在依维莫司组有303例死亡（占83.7%），而在安慰剂组则有151例死亡（82.1%）。依维莫司组的总体存活中位数为7.6个月，而在安慰剂组为7.3个月。疾病控制率（有着完全或部分最佳总体反应或疾病稳定的病人百分比）在依维莫司组为56.1%，而在安慰剂组则为45.1%。

文章的作者写道：“来自这项研究[EVOLVE-1]的结果扩大了晚期HCC第三期研究中的失败名录，它凸显了对这种癌症进行有效治疗的研发所遭遇的挑战。”

研究人员指出，EVOLVE-l以及其它失败的第三期研究提出了数个重要的教训，它们包括要评估来自第二期试验的功效信号是困难的；替代终点——如进展时间、无疾病进展存活及反应率——不能始终一致地预测第三期试验中的总体存活率；及临床及生物学的异质性困难会影响HCC中标靶疗法的性能。“在没有良好表征及得到验证的预测性生物标记时，如果第三期试验是在未经挑选的人群中开展的话，靶制剂可能会继续有失败的高风险。” 

阅读英文原文

Drug everolimus does not improve overall survival in patients with advanced liver cancer

Despite strong preclinical data, the drug everolimus failed to improve overall survival in patients with advanced liver cancer, compared to placebo, according to a study in the July 2 issue of JAMA.

Patients with advanced hepatocellular carcinoma (HCC; a type of liver cancer) have a median overall survival of less than l year, largely because of the absence of effective therapies. The drug sorafenib is the only systemic therapy shown to significantly improve overall survival in advanced HCC; however its benefits are mostly transient and modest, and disease eventually progresses. In preclinical models, everolimus prevented tumor progression and improved survival, according to background information in the article.

Andrew X. Zhu, M.D., Ph.D., of the Massachusetts General Hospital Cancer Center, Harvard Medical School, Boston, and colleagues randomly assigned 546 adults with advanced HCC whose disease progressed during or after sorafenib or who were intolerant of sorafenib to receive everolimus (n = 362) or placebo (n = 184), both given in combination with best supportive care and continued until disease progression or intolerable toxicity. In this phase 3 study, patients were enrolled from 17 countries between May 2010 and March 2012.

The researchers found no significant difference in overall survival between the two groups: there were 303 deaths (83.7 percent) in the everolimus group and 151 deaths (82.1 percent) in the placebo group. Median overall survival was 7.6 months with everolimus, 7.3 months with placebo. The disease control rate (the percentage of patients with a best overall response of complete or partial response or stable disease) was 56.1 percent (everolimus) and 45.1 percent (placebo).

“The results from [this study, EVOLVE-1] extend the list of failed phase 3 studies in advanced HCC, highlighting the challenge of developing effective therapies for this cancer,” the authors write.

The researchers note that EVOLVE-l and the other failed phase 3 studies have provided several important lessons, including that it is difficult to assess efficacy signals from phase 2 trials; surrogate end points such as time to progression, progression-free survival, and response rate inconsistently predict overall survival in phase 3 trials; and clinical and biologic heterogeneity likely affects the performance of targeted therapies in HCC. “In the absence of well-characterized and validated predictive bio-markers, targeted agents will likely continue to have a high risk of failure if phase 3 trials are conducted in unselected populations.”