Neoadjuvant cemiplimab for resectable hepatocellular carcinoma: a single-arm, open-label, phase 2 trial.
Neoadjuvant cemiplimab for resectable hepatocellular carcinoma: a single-arm, open-label, phase 2 trial.
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DOI：
10.1016/s2468-1253(21)00385-x
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发表时间：
2022-03
影响因子：
35.7
通讯作者：
Merad, Miriam
中科院分区：
文献类型：
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作者：
Marron, Thomas U.;Fiel, Maria Isabel;Hamon, Pauline;Fiaschi, Nathalie;Kim, Edward;Ward, Stephen C.;Zhao, Zhen;Kim, Joel;Kennedy, Paul;Gunasekaran, Ganesh;Tabrizian, Parissa;Doroshow, Deborah;Legg, Meredith;Hammad, Ashley;Magen, Assaf;Kamphorst, Alice O.;Shareef, Muhammed;Gupta, Namita T.;Deering, Raquel;Wang, Wei;Wang, Fang;Thanigaimani, Pradeep;Mani, Jayakumar;Troncoso, Leanna;Tabachnikova, Alexandra;Chang, Christie;Akturk, Guray;Buckup, Mark;Hamel, Steven;Ioannou, Giorgio;Hennequin, Clotilde;Jamal, Hajra;Brown, Haley;Bonaccorso, Antoinette;Labow, Daniel;Sarpel, Umut;Rosenbloom, Talia;Sung, Max W.;Kou, Baijun;Li, Siyu;Jankovic, Vladimir;James, Nicola;Ham, Sara C.;Cheung, Hung Kam;Sims, Jennifer S.;Miller, Elizabeth;Bhardwaj, Nina;Thurston, Gavin;Lowy, Israel;Gnjatic, Sacha;Tauli, Bachir;Schwartz, Myron E.;Merad, Miriam
手术切除早期肝细胞癌是标准的临床做法；然而，尽管手术，大多数肿瘤仍会复发，并且没有围手术期干预显示出生存益处。新辅助免疫治疗已在多种肿瘤类型中引起病理反应，并可能降低肝细胞癌术后复发的风险。我们的目的是评估新辅助药西米单抗（一种抗pd -1药物）在可切除肝癌患者中的临床活性。在这项单臂、开放标签、2期试验中，可切除的肝细胞癌（Ib期、II期和IIIb期）患者入组，每3周静脉注射两个周期350 mg新辅助头孢匹抗，然后进行手术切除。符合条件的患者年龄在18岁或以上，确诊为可切除的肝细胞癌，东部肿瘤合作组表现状态为0或1，肝功能正常。如果患者有转移性疾病，如果手术不能治愈，如果他们有已知的需要积极治疗的其他恶性肿瘤，或者如果他们需要全身类固醇治疗或任何其他免疫抑制治疗，则排除患者。切除后，患者在辅助治疗中每3周静脉注射8个周期350 mg的头孢匹单抗。主要终点是病理检查中肿瘤坏死明显（定义为切除肿瘤坏死>70%）。次要终点包括手术延迟、总体缓解的患者比例、CD8+ t细胞密度的变化和不良事件。对所有接受至少一剂头孢匹抗并完成手术切除的患者的肿瘤坏死和反应进行分析；在意向治疗人群中分析安全性和其他终点。在整个治疗过程中，患者接受了治疗前活检和采血。该试验已在ClinicalTrials.gov注册（NCT03916627，队列B），并正在进行中。在2019年8月5日至2020年11月25日期间，共有21名患者入组。所有患者均接受新辅助治疗，20例患者成功切除。在20例切除肿瘤的患者中，4例（20%）有明显的肿瘤坏死。20例患者中有3例（15%）部分缓解，其他所有患者保持病情稳定。20例（95%）患者在新辅助治疗期间出现了任何级别的治疗后不良事件。任何级别最常见的不良事件是天冬氨酸转氨酶升高（4例），血肌酸磷酸激酶升高（3例），便秘（3例）和疲劳（3例）。7例患者出现3级不良事件，包括血肌酸磷酸激酶升高（2例）和低白蛋白血症（1例）。未观察到4级或5级事件。一名患者出现肺炎，导致手术延迟了2周。据我们所知，该报告是迄今为止报道的肝细胞癌新辅助抗pd -1单药治疗的最大临床试验。在该队列中观察到的对西米单抗的病理反应支持更大规模试验的设计，以确定最佳治疗时间，并明确确定术前PD-1阻断对肝癌患者的临床益处。Regeneron药品。
Surgical resection of early stage hepatocellular carcinoma is standard clinical practice; however, most tumours recur despite surgery, and no perioperative intervention has shown a survival benefit. Neoadjuvant immunotherapy has induced pathological responses in multiple tumour types and might decrease the risk of postoperative recurrence in hepatocellular carcinoma. We aimed to evaluate the clinical activity of neoadjuvant cemiplimab (an anti-PD-1) in patients with resectable hepatocellular carcinoma. For this single-arm, open-label, phase 2 trial, patients with resectable hepatocellular carcinoma (stage Ib, II, and IIIb) were enrolled and received two cycles of neoadjuvant cemiplimab 350 mg intravenously every 3 weeks followed by surgical resection. Eligible patients were aged 18 years or older, had confirmed resectable hepatocellular carcinoma, an Eastern Cooperative Oncology Group performance status of 0 or 1, and adequate liver function. Patients were excluded if they had metastatic disease, if the surgery was not expected to be curative, if they had a known additional malignancy requiring active treatment, or if they required systemic steroid treatment or any other immunosuppressive therapy. After resection, patients received an additional eight cycles of cemiplimab 350 mg intravenously every 3 weeks in the adjuvant setting. The primary endpoint was significant tumour necrosis on pathological examination (defined as >70% necrosis of the resected tumour). Secondary endpoints included delay of surgery, the proportion of patients with an overall response, change in CD8+ T-cell density, and adverse events. Tumour necrosis and response were analysed in all patients who received at least one dose of cemiplimab and completed surgical resection; safety and other endpoints were analysed in the intention-to-treat population. Patients underwent pre-treatment biopsies and blood collection throughout treatment. This trial is registered with ClinicalTrials.gov (NCT03916627, Cohort B) and is ongoing. Between Aug 5, 2019, and Nov 25, 2020, 21 patients were enrolled. All patients received neoadjuvant cemiplimab, and 20 patients underwent successful resection. Of the 20 patients with resected tumours, four (20%) had significant tumour necrosis. Three (15%) of 20 patients had a partial response, and all other patients maintained stable disease. 20 (95%) patients had a treatment-emergent adverse event of any grade during the neoadjuvant treatment period. The most common adverse events of any grade were increased aspartate aminotransferase (in four patients), increased blood creatine phosphokinase (in three), constipation (in three), and fatigue (in three). Seven patients had grade 3 adverse events, including increased blood creatine phosphokinase (in two patients) and hypoalbuminaemia (in one). No grade 4 or 5 events were observed. One patient developed pneumonitis, which led to a delay in surgery by 2 weeks. This report is, to our knowledge, the largest clinical trial of a neoadjuvant anti-PD-1 monotherapy reported to date in hepatocellular carcinoma. The observed pathological responses to cemiplimab in this cohort support the design of larger trials to identify the optimal treatment duration and definitively establish the clinical benefit of preoperative PD-1 blockade in patients with hepatocellular carcinoma. Regeneron Pharmaceuticals.