Phase Ib Study of Lenvatinib Plus Pembrolizumab in Patients With Unresectable Hepatocellular Carcinoma
Phase Ib Study of Lenvatinib Plus Pembrolizumab in Patients With Unresectable Hepatocellular Carcinoma
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DOI：
10.1200/jco.20.00808
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发表时间：
2020-09-10
影响因子：
45.3
通讯作者：
Llovet, Josep M.
中科院分区：
文献类型：
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作者：
Finn, Richard S.;Ikeda, Masafumi;Llovet, Josep M.
乐伐替尼（一种多激酶抑制剂）对肿瘤微环境的免疫调节作用可能有助于在肝细胞癌（HCC）中与程序性死亡受体-1（PD-1）信号传导抑制剂联合使用时的抗肿瘤活性。我们报告了乐伐替尼联合派姆单抗（一种抗PD-1抗体）治疗不可切除的HCC（uHCC）的Ib期研究结果。患者和方法在这项开放标签的多中心研究中，uHCC患者在21天周期的第1天接受乐伐替尼（体重≥ 60 kg，12 mg; < 60 kg，8 mg）每日口服和帕博利珠单抗200 mg静脉注射。该研究包括剂量限制性毒性（DLT）阶段和扩展阶段（一线患者）。主要目的是安全性/耐受性（DLT阶段）、客观缓解率（ORR）和缓解持续时间（DOR），根据独立影像学审查（IIR;扩展阶段），采用改良的RECIST（mRECIST）和RECIST版本1.1（v1.1）。结果共纳入104例患者。DLT阶段未报告DLT（n = 6）; 100例患者（扩展阶段;包括DLT阶段的n = 2）既往未接受过全身治疗，患有巴塞罗那临床肝癌B期（n = 29）或C期疾病（n = 71）。在数据截止时，37%的患者仍在接受治疗。中位随访时间为10.6个月（95% CI，9.2 - 11.5个月）。根据mRECIST，IIR确认的ORR为46.0%（95% CI，36.0%-56.3%），根据RECIST v1.1，确认的ORR为36.0%（95% CI，26.6%-46.2%）。根据mRECIST，IIR的中位DOR为8.6个月（95% CI，6.9个月至无法估计[NE]），根据RECIST v1.1，中位DOR为12.6个月（95% CI，6.9个月至NE）。根据mRECIST，IIR的中位无进展生存期为9.3个月，根据RECIST v1.1，中位无进展生存期为8.6个月。中位总生存期为22个月。67%的患者发生≥ 3级治疗相关不良事件（5级，3%）。未发现新的安全性信号。结论乐伐替尼联合帕博利珠单抗对uHCC有较好的抗肿瘤作用。毒性是可控的，没有意外的安全性信号。
PURPOSE The immunomodulatory effect of lenvatinib (a multikinase inhibitor) on tumor microenvironments may contribute to antitumor activity when combined with programmed death receptor-1 (PD-1) signaling inhibitors in hepatocellular carcinoma (HCC). We report results from a phase Ib study of lenvatinib plus pembrolizumab (an anti-PD-1 antibody) in unresectable HCC (uHCC). PATIENTS AND METHODS In this open-label multicenter study, patients with uHCC received lenvatinib (bodyweight >= 60 kg, 12 mg; < 60 kg, 8 mg) orally daily and pembrolizumab 200 mg intravenously on day 1 of a 21-day cycle. The study included a dose-limiting toxicity (DLT) phase and an expansion phase (first-line patients). Primary objectives were safety/tolerability (DLT phase), and objective response rate (ORR) and duration of response (DOR) by modified RECIST (mRECIST) and RECIST version 1.1 (v1.1) per independent imaging review (IIR; expansion phase). RESULTS A total of 104 patients were enrolled. No DLTs were reported (n = 6) in the DLT phase; 100 patients (expansion phase; included n = 2 from DLT phase) had received no prior systemic therapy and had Barcelona Clinic Liver Cancer stage B (n = 29) or C disease (n = 71). At data cutoff, 37% of patients remained on treatment. Median duration of follow-up was 10.6 months (95% CI, 9.2 to 11.5 months). Confirmed ORRs by IIR were 46.0% (95% CI, 36.0% to 56.3%) per mRECIST and 36.0% (95% CI, 26.6% to 46.2%) per RECIST v1.1. Median DORs by IIR were 8.6 months (95% CI, 6.9 months to not estimable [NE]) per mRECIST and 12.6 months (95% CI, 6.9 months to NE) per RECIST v1.1. Median progression-free survival by IIR was 9.3 months per mRECIST and 8.6 months per RECIST v1.1. Median overall survival was 22 months. Grade >= 3 treatment-related adverse events occurred in 67% (grade 5, 3%) of patients. No new safety signals were identified. CONCLUSION Lenvatinib plus pembrolizumab has promising antitumor activity in uHCC. Toxicities were manageable, with no unexpected safety signals.