Kim Bo Hyun, Park Hee Chul, Kim Tae Hyun, Koh Young-Hwan, Hong Jung Yong, Cho Yuri, Sinn Dong Hyun, Park Boram, Park Joong-Won
Center for Liver and Pancreatobiliary Cancer, National Cancer Center, Goyang, Republic of Korea.
Department of Radiation Oncology, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Republic of Korea.
JHEP Rep. 2023 Dec 21;6(4):100991. doi: 10.1016/j.jhepr.2023.100991. eCollection 2024 Apr.
Nivolumab was the first immune checkpoint inhibitor approved for hepatocellular carcinoma (HCC). External beam radiation therapy (EBRT) is locally effective and may enhance the effectiveness of immunotherapy. This study investigated the efficacy and safety of concurrent nivolumab and EBRT in HCC with macrovascular invasion.
In this phase II multicenter trial, patients with HCC and macrovascular invasion were concurrently treated with intravenous nivolumab (3 mg/kg every 2 weeks) and EBRT, followed by maintenance nivolumab until progression or unacceptable toxicity. Primary endpoints were progression-free survival (PFS) and safety, and secondary endpoints were overall survival, time-to-progression, objective response rate, and disease control rate.
Between January 2020 and June 2021, 50 patients (male 84%, median age 62.5) were enrolled; 47 (94.0%) and 13 (26.0%) with portal (Vp1/2, n = 21; Vp3, n = 23; Vp4, n = 3) and hepatic vein invasion, respectively. Patients received EBRT (median dose: 50 [IQR 43-50] Gy) after the first nivolumab dose. The median number of nivolumab doses was 8.5. Median PFS was 5.6 (90% CI 3.6-9.9) months. Median overall survival and time-to-progression were 15.2 (90% CI 10.8-19.6) and 5.6 (90% CI 3.6-9.9) months, respectively. The objective response rate and disease control rate were 36.0% and 74.0%, respectively. The median duration of response was 9.9 months. Of 35 patients with follow-up data, 23 received subsequent systemic treatment, including atezolizumab-bevacizumab, sorafenib, lenvatinib, and regorafenib. Treatment-related any grade adverse events (AEs) and grade 3/4 AEs occurred in 40 (80.0%) and 6 (12.0%) patients, respectively. Common treatment-related AEs included pruritus (38.0%) and rash (16.0%), with no treatment-related deaths.
Concurrent nivolumab therapy and EBRT showed encouraging PFS with acceptable safety in patients with advanced HCC and macrovascular invasion.
Immune checkpoint inhibitors, the standard care for advanced hepatocellular carcinoma (HCC), show relatively poor therapeutic effects in patients with advanced HCC and macrovascular invasion. In this investigator-initiated phase II study, we, for the first time, show that concurrent external beam radiation therapy with nivolumab, an immune checkpoint inhibitor, led to encouraging progression-free survival in patients with HCC and macrovascular invasion. The concurrent treatment was tolerable without significant safety concerns. Further randomized studies investigating the combination of immunotherapy and external beam radiation therapy are required.
NCT04611165.
纳武利尤单抗是首个被批准用于肝细胞癌（HCC）的免疫检查点抑制剂。外照射放疗（EBRT）在局部具有疗效，且可能增强免疫治疗的效果。本研究调查了纳武利尤单抗与EBRT联合用于伴有大血管侵犯的HCC的疗效和安全性。
在这项II期多中心试验中，伴有大血管侵犯的HCC患者同时接受静脉注射纳武利尤单抗（每2周3mg/kg）和EBRT治疗，随后接受纳武利尤单抗维持治疗直至疾病进展或出现不可接受的毒性反应。主要终点为无进展生存期（PFS）和安全性，次要终点为总生存期、至疾病进展时间、客观缓解率和疾病控制率。
2020年1月至2021年6月期间，共纳入50例患者（男性占84%，中位年龄62.5岁）；分别有47例（94.0%）和13例（26.0%）伴有门静脉（Vp1/2，n = 21；Vp3，n = 23；Vp4，n = 3）和肝静脉侵犯。患者在首次使用纳武利尤单抗后接受了EBRT（中位剂量：50 [IQR 43 - 50] Gy）。纳武利尤单抗的中位给药次数为8.5次。中位PFS为5.6（90% CI 3.6 - 9.9）个月。中位总生存期和至疾病进展时间分别为15.2（90% CI 10.8 - 19.6）个月和5.6（90% CI 3.6 - 9.9）个月。客观缓解率和疾病控制率分别为36.0%和74.0%。中位缓解持续时间为9.9个月。在有随访数据的35例患者中，23例接受了后续的全身治疗，包括阿替利珠单抗-贝伐珠单抗、索拉非尼、仑伐替尼和瑞戈非尼。治疗相关的任何级别不良事件（AE）和3/4级AE分别发生在40例（80.0%）和6例（12.0%）患者中。常见的治疗相关AE包括瘙痒（38.0%）和皮疹（16.0%），无治疗相关死亡病例。
纳武利尤单抗与EBRT联合治疗在伴有大血管侵犯的晚期HCC患者中显示出令人鼓舞的PFS，且安全性可接受。
免疫检查点抑制剂作为晚期肝细胞癌（HCC）的标准治疗方案，在伴有大血管侵犯的晚期HCC患者中疗效相对较差。在这项研究者发起的II期研究中，我们首次表明，免疫检查点抑制剂纳武利尤单抗与外照射放疗联合，可使伴有大血管侵犯的HCC患者获得令人鼓舞的无进展生存期。联合治疗耐受性良好，无重大安全问题。需要进一步开展随机研究以探索免疫治疗与外照射放疗联合的方案。
NCT0
