Chan D L, Rodriguez-Freixinos V, Doherty M, Wasson K, Iscoe N, Raskin W, Hallet J, Myrehaug S, Law C, Thawer A, Nguyen K, Singh S
Sunnybrook Health Sciences Centre, Toronto, ON, Canada.
Sunnybrook Health Sciences Centre, Toronto, ON, Canada.
Eur J Cancer. 2022 Jul;169:74-81. doi: 10.1016/j.ejca.2022.03.029. Epub 2022 May 2.
Higher grade neuroendocrine neoplasm (NENs) continues to pose a treatment dilemma, with the optimal treatment undefined. Although immunotherapy has revolutionised the treatment of many cancers, its role in NENs remains unclear. We aimed to investigate the efficacy and safety of avelumab, a PD-L1-directed antibody, in patients with advanced unresectable/metastatic higher grade NENs.
NET001 and NET002 are phase II studies investigating avelumab (NCT03278405 and NCT03278379). Eligible patients had unresectable and/or metastatic WHO G2-3 NENs from a gastroenteropancreatic (GEP) source or a bronchial primary (excluding typical carcinoid) and 0-2 prior lines of systemic therapy (excluding SSAs). Patients were treated with avelumab 10 mg/kg intravenously every two weeks for 26 cycles. NET001 investigated G3 poorly differentiated GEP neuroendocrine carcinomas (NECs) and bronchial small/large cell NEC, whereas NET002 investigated G2-3 well-differentiated GEPNETs and bronchial atypical carcinoids. The primary endpoint in both trials was overall response rate (ORR) by RECIST v1.1; secondary endpoints included progression-free survival, overall survival, disease control rate at six months and toxicity.
Twenty-seven patients were enrolled (21 GEP, 6 lung; 10 in NET-001, 17 in NET-002); median age 64 (range 37-80), 30% ECOG PS 1-2 and 78% received 1+ lines of prior therapy. The median Ki-67 index was 35% (range 10-100). Twelve of the twenty-seven patients had died at the time of data lock. The median time on treatment was 85 days (seven cycles). No objective responses were observed. Stable disease was achieved in 33% of patients, and the disease control rate at 6 mo was 21%. The median PFS was 3.3 months (range 1.2-24.6), and the median OS was 14.2 months. Treatment-related adverse events (all grades) occurred in 58% of patients. Three patients had treatment-related grade 3-4 AEs leading to treatment discontinuation (immune-related hepatitis n = 2 and infusion-related reaction n = 1).
Single-agent PD-L1 blockade with avelumab showed limited antitumour activity in patients with G2-3 NENs. Correlative studies are underway. Further studies are needed to explore the role of dual immunotherapy and other combinations in this population with few treatment alternatives.
高级别神经内分泌肿瘤（NENs）仍然是一个治疗难题，最佳治疗方案尚未明确。尽管免疫疗法已经彻底改变了许多癌症的治疗方式，但其在NENs中的作用仍不明确。我们旨在研究抗程序性死亡配体1（PD-L1）抗体阿维鲁单抗在晚期不可切除/转移性高级别NENs患者中的疗效和安全性。
NET001和NET002是研究阿维鲁单抗的II期试验（NCT03278405和NCT03278379）。符合条件的患者患有来自胃肠胰（GEP）来源或支气管原发性（不包括典型类癌）的不可切除和/或转移性世界卫生组织（WHO）G2-3级NENs，且既往接受过0-2线全身治疗（不包括生长抑素类似物）。患者接受阿维鲁单抗10mg/kg静脉注射，每两周一次，共26个周期。NET001研究G3级低分化GEP神经内分泌癌（NECs）和支气管小/大细胞NEC，而NET002研究G2-3级高分化GEP神经内分泌瘤（NETs）和支气管非典型类癌。两项试验的主要终点均为根据实体瘤疗效评价标准（RECIST）v1.1的总缓解率（ORR）；次要终点包括无进展生存期、总生存期、6个月时的疾病控制率和毒性。
共入组27例患者（21例GEP，6例肺部；NET-001组10例，NET-002组17例）；中位年龄64岁（范围37-80岁），30%的东部肿瘤协作组（ECOG）体能状态评分为1-2，78%的患者接受过1线及以上的既往治疗。中位Ki-67指数为35%（范围10%-100%）。在数据锁定时，27例患者中有12例死亡。中位治疗时间为85天（7个周期）。未观察到客观缓解。33%的患者病情稳定，6个月时的疾病控制率为21%。中位无进展生存期为3.3个月（范围1.2-24.6个月），中位总生存期为14.2个月。58%的患者发生了与治疗相关的不良事件（所有级别）。3例患者发生了与治疗相关的3-4级不良事件导致治疗中断（免疫相关肝炎2例，输液相关反应1例）。
阿维鲁单抗单药PD-L1阻断在G2-3级NENs患者中显示出有限的抗肿瘤活性。相关研究正在进行中。由于该人群的治疗选择较少，因此需要进一步研究探索双免疫疗法和其他联合方案的作用。
