Lessons learned: Combination therapies in patients with hepatocellular carcinoma can be associated with overlapping toxicity and are therefore poorly tolerated.Using sorafenib at the maximum tolerated dose can lead to a higher incidence of toxicities. Consequently, combination studies might evaluate sorafenib at alternative schedules or doses to improve tolerance, recognizing this could affect sorafenib efficacy.Although this combination was poorly tolerated, it does not exclude further evaluation of new-generation immunomodulator drugs or immune checkpoint inhibitors in the hope of optimizing tolerance and safety.
Background: Sorafenib is the standard treatment for advanced hepatocellular carcinoma (HCC), and to date, no combination therapy has demonstrated superior survival compared with sorafenib alone. The immunosuppressive microenvironment in HCC is a negative predictor for survival. Lenalidomide is an immunomodulator and antiangiogenic agent, with limited single-agent efficacy in HCC. Based on these data, we designed a phase I study of sorafenib plus lenalidomide to determine the safety and preliminary antitumor activity of this combination.
Methods: This was an open-label, phase I study with a 3+3 dose escalation/de-escalation design. The starting dose of sorafenib was 400 mg p.o. b.i.d. and of lenalidomide was 15 mg p.o. daily with a planned dose escalation by 5 mg per cohort up to 25 mg daily. Dose de-escalation was planned to a sorafenib dose of 400 mg p.o. daily combined with two doses of lenalidomide: 10 mg p.o. daily for a 28-day cycle (cohort 1) and 10 mg p.o. daily for a 21- or 28-day cycle (cohort 2). Patients with cirrhosis, a Child-Pugh score of A-B7, and no previous systemic therapy were eligible.
Results: Five patients were enrolled. Their median age was 56 years (range 39-61), and the ECOG status was 0-2. Four patients were treated at dose level (DL) 1. Because of the poor tolerance to the combination associated with grade 2 toxicities, one more patient was treated at DL -1. No dose-limiting toxicity was observed as specified per protocol. The most common toxicities were nausea, anorexia, pruritus, elevated liver enzymes, and elevated bilirubin. Three patients experienced one or more of the following grade 3 toxicities: fatigue (DL 1), increased bilirubin (DL 1), skin desquamation (DL -1), and elevated transaminase levels (DL 1). The median duration of therapy was 1 cycle (range 1-3). All patients discontinued the study, 4 because of progressive disease and 1 by patient preference. The best confirmed response was progressive disease. The median progression-free survival was 1.0 month (95% confidence interval 0.9-2.8), and the median overall survival was 5.9 months (95% confidence interval 3.68-23.4).
Conclusion: In our small study, the combination of lenalidomide and sorafenib was poorly tolerated and showed no clinical activity. Although the study was closed early because of toxicity concerns, future studies assessing combinations of sorafenib with new-generation immunomodulator drugs or other immunomodulatory agents, should consider lower starting doses of sorafenib to avoid excessive toxicity.
作者总结
经验
• 对肝细胞癌患者采用联合治疗往往可造成毒性叠加, 因而耐受不佳。
• 使用最大耐受剂量的索拉非尼可导致毒性事件发生率较高。因此, 联合方案的研究也许可以对能够改善耐受性的索拉非尼的备选方案或剂量进行评价, 但应该认识到这可能影响索拉非尼的有效性。
• 尽管这一联合方案耐受不佳, 但并不排除对新一代免疫调节剂药物或免疫检查点抑制剂进行进一步评价, 可望优化耐受性和安全性。
摘要
背景. 索拉非尼是晚期肝细胞癌 (HCC) 的标准治疗, 此外, 迄今为止尚未证实联合方案优于索拉非尼单药治疗。HCC 的免疫抑制微环境是生存的负向预测因素。来那度胺是免疫调节剂和抗血管生成制剂, 单药治疗用于 HCC 的疗效很有限。基于这些数据, 我们设计了一项索拉非尼联合来那度胺治疗的 I 期研究, 旨在确定这一联合方案的安全性和初步抗肿瘤活性。
方法. 本研究为开放标签 I 期研究, 采用 3+3 剂量递增/递减设计。索拉非尼的起始剂量为 400 mg 口服, 每日两次; 来那度胺的起始剂量为 15 mg 口服, 每日一次, 计划以 5 mg 为单位上调剂量, 直至 25 mg 每天。计划对索拉非尼 (400 mg 口服, 每日一次) 联合两个剂量的来那度胺进行剂量递减: 队列 1 为 10 mg 口服, 每日一次, 28 天为一周期; 队列 2 为10 mg 口服, 每日一次, 21 天或 28 天为一周期。肝硬化、Child-Pugh评分为A∼B7, 以及既往未接受过系统治疗的患者可入选。
结果. 共入组5例患者。中位年龄为56岁 (范围: 39∼61), ECOG状态评分为 0∼2分。4 例患者接受剂量水平 (DL) 1 治疗。另有 1 例患者由于对联合治疗耐受较差, 发生了 2 级毒性事件, 因此接受了 DL-1 治疗。未观察到方案定义的剂量限制毒性。最常见的毒性为恶心、厌食、瘙痒、肝酶水平升高和胆红素水平升高。 3 例患者发生了≥ 1 起 3 级毒性事件, 包括: 乏力 (DL1)、胆红素水平升高 (DL1)、皮肤脱屑 (DL-1), 和转氨酶水平升高 (DL1)。中位疗程为 1 周期 (范围: 1∼3)。所有患者均终止研究, 4 例是由于疾病进展, 1 例是由于患者选择。确认的最佳治疗反应为疾病进展。中位无进展生存为 1.0 个月 (95%置信区间: 0.9∼2.8), 中位总生存为5.9 个月 (95%置信区间: 3.68∼23.4)。
结论. 本项小型研究中, 来那度胺与索拉非尼联合的方案耐受不佳, 且未显示出临床活性。尽管本研究因毒性问题提早终止, 但在未来评估索拉非尼与新一代免疫调节药物或其他免疫调节制剂的联合应用时, 应考虑起始采用较低剂量的索拉非尼以避免过多的毒性事件。The Oncologist 2016;21:664–665d
Trial registration: ClinicalTrials.gov NCT01348503.
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