Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.
Asan Medical Center, University of Ulsan College of Medicine, Seoul, South Korea.
Lancet Oncol. 2020 Jun;21(6):808-820. doi: 10.1016/S1470-2045(20)30156-X.
Dual blockade of PD-L1 and VEGF has enhanced anticancer immunity through multiple mechanisms and augmented antitumour activity in multiple malignancies. We aimed to assess the efficacy and safety of atezolizumab (anti-PD-L1) alone and combined with bevacizumab (anti-VEGF) in patients with unresectable hepatocellular carcinoma.
GO30140 is an open-label, multicentre, multiarm, phase 1b study that enrolled patients at 26 academic centres and community oncology practices in seven countries worldwide. The study included five cohorts, and the two hepatocellular carcinoma cohorts, groups A and F, are described here. Inclusion criteria for these two groups included age 18 years and older; histologically, cytologically, or clinically (per American Association for the Study of Liver Diseases criteria) confirmed unresectable hepatocellular carcinoma that was not amenable to curative treatment; no previous systemic treatment; and Eastern Cooperative Oncology Group performance status of 0 or 1. In group A, all patients received atezolizumab (1200 mg) and bevacizumab (15 mg/kg) intravenously every 3 weeks. In group F, patients were randomly assigned (1:1) to receive intravenous atezolizumab (1200 mg) plus intravenous bevacizumab (15 mg/kg) every 3 weeks or atezolizumab alone by interactive voice-web response system using permuted block randomisation (block size of two) and stratification factors of geographical region; macrovascular invasion, extrahepatic spread, or both; and baseline α-fetoprotein concentration. Primary endpoints were confirmed objective response rate in all patients who received the combination treatment for group A and progression-free survival in the intention-to-treat population in group F, both assessed by an independent review facility according to Response Evaluation Criteria in Solid Tumors version 1.1. In both groups, safety was assessed in all patients who received at least one dose of any study treatment. This study is registered with ClinicalTrials.gov, NCT02715531, and is closed to enrolment.
In group A, 104 patients were enrolled between July 20, 2016, and July 31, 2018, and received atezolizumab plus bevacizumab. With a median follow-up of 12·4 months (IQR 8·0-16·2), 37 (36%; 95% CI 26-46) of 104 patients had a confirmed objective response. The most common grade 3-4 treatment-related adverse events were hypertension (13 [13%]) and proteinuria (seven [7%]). Treatment-related serious adverse events occurred in 25 (24%) patients and treatment-related deaths in three (3%) patients (abnormal hepatic function, hepatic cirrhosis, and pneumonitis). In group F, 119 patients were enrolled and randomly assigned (60 to atezolizumab plus bevacizumab; 59 to atezolizumab monotherapy) between May 18, 2018, and March 7, 2019. With a median follow-up of 6·6 months (IQR 5·5-8·5) for the atezolizumab plus bevacizumab group and 6·7 months (4·2-8·2) for the atezolizumab monotherapy group, median progression-free survival was 5·6 months (95% CI 3·6-7·4) versus 3·4 months (1·9-5·2; hazard ratio 0·55; 80% CI 0·40-0·74; p=0·011). The most common grade 3-4 treatment-related adverse events in group F were hypertension (in three [5%] patients in the atezolizumab plus bevacizumab group; none in the atezolizumab monotherapy group) and proteinuria (in two [3%] patients in the atezolizumab plus bevacizumab group; none in the atezolizumab monotherapy group). Treatment-related serious adverse events occurred in seven (12%) patients in the atezolizumab plus bevacizumab group and two (3%) patients in the atezolizumab monotherapy group. There were no treatment-related deaths.
Our study shows longer progression-free survival with a combination of atezolizumab plus bevacizumab than with atezolizumab alone in patients with unresectable hepatocellular carcinoma not previously treated with systemic therapy. Therefore, atezolizumab plus bevacizumab might become a promising treatment option for these patients. This combination is being compared with standard-of-care sorafenib in a phase 3 trial.
F Hoffmann-La Roche/Genentech.
PD-L1 和 VEGF 的双重阻断通过多种机制增强了抗癌免疫，并增强了多种恶性肿瘤的抗肿瘤活性。我们旨在评估阿特珠单抗（抗 PD-L1）单药联合贝伐珠单抗（抗 VEGF）在不可切除肝细胞癌患者中的疗效和安全性。
GO30140 是一项开放标签、多中心、多臂、1b 期研究，在全球 7 个国家的 26 个学术中心和社区肿瘤学实践中招募了患者。该研究包括 5 个队列，我们在此描述了两个肝细胞癌队列，队列 A 和 F。这两组的纳入标准包括年龄 18 岁及以上；组织学、细胞学或临床（根据美国肝病研究协会标准）证实为不可切除的肝细胞癌，不适于根治性治疗；无先前的系统治疗；和东部肿瘤协作组表现状态为 0 或 1。在队列 A 中，所有患者均接受阿特珠单抗（1200mg）和贝伐珠单抗（15mg/kg）每 3 周静脉输注一次。在队列 F 中，患者以 1:1 的比例随机分配（按交互语音网络响应系统）接受静脉注射阿特珠单抗（1200mg）加静脉注射贝伐珠单抗（15mg/kg），每 3 周一次，或单独使用贝伐珠单抗，使用随机化块大小为 2 和分层因素为地理区域、大血管侵犯、肝外扩散或两者均有，以及基线α-胎蛋白浓度。主要终点是所有接受联合治疗的队列 A 患者的确认客观缓解率，以及意向治疗人群的无进展生存期，均根据实体瘤反应评估标准 1.1 由独立审查机构评估。在两组中，均评估了至少接受一次任何研究治疗的所有患者的安全性。这项研究在 ClinicalTrials.gov 上注册，编号为 NCT02715531，现已关闭入组。
在队列 A 中，2016 年 7 月 20 日至 2018 年 7 月 31 日期间共招募了 104 名患者，接受了阿特珠单抗联合贝伐珠单抗治疗。中位随访时间为 12.4 个月（IQR 8.0-16.2），104 名患者中有 37 名（36%；95%CI 26-46）有确认的客观缓解。最常见的 3-4 级治疗相关不良事件为高血压（13[13%]）和蛋白尿（7[7%]）。25 名（24%）患者发生治疗相关严重不良事件，3 名（3%）患者发生治疗相关死亡（肝功能异常、肝硬化和肺炎）。在队列 F 中，2018 年 5 月 18 日至 2019 年 3 月 7 日期间共招募了 119 名患者，并随机分配（60 名接受阿特珠单抗联合贝伐珠单抗治疗；59 名接受阿特珠单抗单药治疗）。对于阿特珠单抗联合贝伐珠单抗组，中位无进展生存期为 5.6 个月（95%CI 3.6-7.4），阿特珠单抗单药组为 3.4 个月（1.9-5.2；风险比 0.55；95%CI 0.40-0.74；p=0.011）。队列 F 中最常见的 3-4 级治疗相关不良事件为高血压（阿特珠单抗联合贝伐珠单抗组 3 例[5%]；阿特珠单抗单药组无）和蛋白尿（阿特珠单抗联合贝伐珠单抗组 2 例[3%]；阿特珠单抗单药组无）。阿特珠单抗联合贝伐珠单抗组有 7 名（12%）患者发生治疗相关严重不良事件，阿特珠单抗单药组有 2 名（3%）患者发生治疗相关死亡。没有治疗相关死亡。
我们的研究表明，在未接受系统治疗的不可切除肝细胞癌患者中，与阿特珠单抗单药治疗相比，阿特珠单抗联合贝伐珠单抗可延长无进展生存期。因此，阿特珠单抗联合贝伐珠单抗可能成为这些患者有前途的治疗选择。该联合治疗正在与标准治疗索拉非尼进行 3 期临床试验比较。
F 霍夫曼-拉罗氏/基因泰克。
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