恩杂鲁胺联合或不联合索拉非尼治疗晚期肝细胞癌的Ib期研究。
Phase Ib Study of Enzalutamide with or Without Sorafenib in Patients with Advanced Hepatocellular Carcinoma.
作者信息
Harding James J, Kelley Robin K, Tan Benjamin, Capanu Marinela, Do Gian Kinh, Shia Jinru, Chou Joanne F, Ferrer Christine S, Boussayoud Chayma, Muenkel Kerri, Yarmohammadi Hooman, El Dika Imane, Khalil Danny N, Ruiz Carmen, Rodriguez-Lee Mariam, Kuhn Peter, Wilton John, Iyer Renuka, Abou-Alfa Ghassan K
机构信息
Department of Medicine, Memorial Sloan Kettering Cancer Center, Weill Cornell Medical College, New York, New York, USA.
Department of Medicine, Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco, California, USA.
出版信息
Oncologist. 2020 Dec;25(12):e1825-e1836. doi: 10.1634/theoncologist.2020-0521. Epub 2020 Jul 2.
LESSONS LEARNED
Androgen receptor as assessed by immunohistochemistry is expressed in a high proportion of patients with hepatocellular carcinoma (HCC). Enzalutamide at 160 mg orally daily is safe and tolerable in patients with advanced HCC but has no single-agent antitumor activity. Enzalutamide, a CYP3A4 inducer, at a standard dose of 160 mg reduces the exposure of sorafenib, a CYP3A4 substrate. Enzalutamide and sorafenib is safe and tolerable in patients with advanced HCC, but the addition of enzalutamide to sorafenib did not enhance the antitumor activity of sorafenib.
BACKGROUND
Androgen receptor (AR) interference is deleterious to hepatocellular carcinoma (HCC) in preclinical models.
METHODS
This is a multicenter, phase Ib study of enzalutamide ± sorafenib in patients with advanced HCC. In part 1, a 3 + 3 dose de-escalation design with expansion established the recommended phase II dose (RP2D) of enzalutamide in patients in whom sorafenib treatment had failed. In part 2, a 3 + 3 dose escalation with expansion established the safety of enzalutamide with sorafenib in treatment-naive patients with HCC. Secondary objectives included objective response rate (ORR), progression-free survival (PFS), overall survival (OS), pharmacokinetics (PK), and determination of AR expression by immunohistochemistry. A 7-day run-in with sorafenib alone in part 2 allowed assessment of the impact of enzalutamide on sorafenib pharmacokinetics.
RESULTS
In part 1, 16 patients received enzalutamide 160 mg daily. No dose-limiting toxicity (DLT) occurred; 1 patient required dose reduction. Responses were not observed; median PFS and OS were 1.8 (95% confidence interval [CI]: 1.6-3.6) and 7 (95% CI: 3.6 to not reached [NR]) months, respectively. In part 2, patients received sorafenib 400 mg daily (4) or twice a day (8) both with enzalutamide at the recommended phase II dose-no DLTs were observed. ORR was 10% (95% CI: 0.3-44.5), and median PFS and OS were 2.9 (95% CI: 1.6 to NR) and 6.7 (95% CI: 4.6 to NR) months, respectively. Enzalutamide reduced sorafenib exposure by 60%. Tumor AR expression did not associate with outcome.
CONCLUSION
Enzalutamide is ineffective in HCC; further development is not supported by this study.
经验教训
通过免疫组织化学评估发现，雄激素受体在高比例的肝细胞癌（HCC）患者中表达。对于晚期HCC患者，每日口服160mg恩杂鲁胺是安全且可耐受的，但无单药抗肿瘤活性。恩杂鲁胺作为一种细胞色素P450 3A4（CYP3A4）诱导剂，标准剂量160mg可降低CYP3A4底物索拉非尼的血药浓度。恩杂鲁胺联合索拉非尼治疗晚期HCC患者安全且可耐受，但在索拉非尼基础上加用恩杂鲁胺并未增强索拉非尼的抗肿瘤活性。
背景
在临床前模型中，雄激素受体（AR）干扰对肝细胞癌（HCC）有害。
方法
这是一项关于恩杂鲁胺±索拉非尼治疗晚期HCC患者的多中心1b期研究。在第1部分，采用3 + 3剂量递减设计并扩展，确定了索拉非尼治疗失败患者中恩杂鲁胺的推荐II期剂量（RP2D）。在第2部分，采用3 + 3剂量递增设计并扩展，确定了恩杂鲁胺联合索拉非尼在初治HCC患者中的安全性。次要目标包括客观缓解率（ORR）、无进展生存期（PFS）、总生存期（OS）、药代动力学（PK）以及通过免疫组织化学测定AR表达。在第2部分中，先单独使用索拉非尼进行7天导入期，以评估恩杂鲁胺对索拉非尼药代动力学的影响。
结果
在第1部分，16例患者每日接受160mg恩杂鲁胺治疗。未发生剂量限制性毒性（DLT）；1例患者需要减量。未观察到缓解；中位PFS和OS分别为1.8（95%置信区间[CI]：1.6 - 3.6）个月和7（95%CI：3.6至未达到[NR]）个月。在第2部分，患者每日接受400mg索拉非尼（4例）或每日两次索拉非尼（8例）联合推荐II期剂量的恩杂鲁胺治疗，均未观察到DLT。ORR为10%（95%CI：0.3 - 44.5），中位PFS和OS分别为2.9（95%CI：1.6至NR）个月和6.7（95%CI：4.6至NR）个月。恩杂鲁胺使索拉非尼血药浓度降低60%。肿瘤AR表达与预后无关。
结论
恩杂鲁胺对HCC无效；本研究不支持其进一步研发。
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