Pavel Marianne, Lahner Harald, Hörsch Dieter, Rinke Anja, Denecke Timm, Koch Arend, Regnault Benjamin, Helbig Dorit, Hoffmanns Philipp, Raderer Markus
Department of Hepatology and Gastroenterology, Charité-Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health (BIH), Berlin, Germany.
Department of Medicine 1, Friedrich Alexander University Erlangen-Nuernberg, University Hospital Erlangen, Erlangen, Germany.
Oncologist. 2024 May 3;29(5):e643-e654. doi: 10.1093/oncolo/oyad325.
In advanced neuroendocrine tumors (NET), antiproliferative treatment options beyond somatostatin analogs remain limited. Temozolomide (TMZ) has shown efficacy in NET alone or combined with other drugs.
SONNET (NCT02231762) was an open, multicenter, prospective, phase II study to evaluate lanreotide autogel 120 mg (LAN) plus TMZ in patients with progressive advanced/metastatic grade 1/2 gastroenteropancreatic (GEP) NET or of unknown primary. Patients could be enrolled at first-line or higher therapy line. The primary endpoint was disease control rate ([DCR], rate of stable disease [SD], partial [PR], and complete response [CR]) at 6 months of LAN and TMZ. Patients with nonfunctioning (NF) NET without progression at 6 months were randomized to 6-month LAN maintenance or watch and wait, patients with functioning (F)-NET with clinical benefit (PR, SD) continued on LAN.
Fifty-seven patients were recruited. The majority of patients received the study drug at second or higher treatment line and had an NET G2. DCR at 6 months LAN and TMZ was 73.5%. After 6 months of further LAN maintenance, 54.5% of patients with F-NET and 71.4% with NF-NET had SD or PR vs 41.7% with NF-NET on observation only. LAN and TMZ were effective in all subgroups analyzed. At 12 months of follow-up, median progression-free survival was 11.1 months. Median serum chromogranin A decreased except in NF-NET on observation. O6-methylguanine DNA methyltransferase promoter methylation appeared to better reflect TMZ response than loss of gene expression. During combination therapy, the most frequent treatment-emergent adverse events grade 3/4 reported were nausea (14%), thrombocytopenia (12.3%), and neutropenia (8.8%). Four deaths were reported resulting from severe adverse events not considered related to study medication.
LAN plus TMZ is a treatment option for patients with progressive GEP-NET with more aggressive biological profile showing a manageable safety profile.
在晚期神经内分泌肿瘤（NET）中，除生长抑素类似物外的抗增殖治疗选择仍然有限。替莫唑胺（TMZ）已显示出对NET单独使用或与其他药物联合使用的疗效。
SONNET（NCT02231762）是一项开放、多中心、前瞻性II期研究，旨在评估120mg兰瑞肽长效注射凝胶（LAN）联合TMZ用于进展期高级别/转移性1/2级胃肠胰（GEP）NET或原发灶不明的患者。患者可在一线或更高治疗线入组。主要终点是LAN和TMZ治疗6个月时的疾病控制率（[DCR]，疾病稳定率[SD]、部分缓解[PR]和完全缓解[CR]率）。6个月时无进展的无功能（NF）NET患者被随机分为接受6个月LAN维持治疗或观察等待，有功能（F）-NET且有临床获益（PR、SD）的患者继续接受LAN治疗。
招募了57例患者。大多数患者在二线或更高治疗线接受研究药物治疗，且为NET G2。LAN和TMZ治疗6个月时的DCR为73.5%。进一步LAN维持治疗6个月后，54.5%的F-NET患者和71.4%的NF-NET患者病情稳定或部分缓解，而仅接受观察的NF-NET患者这一比例为41.7%。LAN和TMZ在所有分析的亚组中均有效。随访12个月时，中位无进展生存期为11.1个月。除观察中的NF-NET外，血清嗜铬粒蛋白A中位数下降。O6-甲基鸟嘌呤DNA甲基转移酶启动子甲基化似乎比基因表达缺失更能反映TMZ反应。联合治疗期间，报告的最常见3/4级治疗中出现的不良事件为恶心（14%）、血小板减少（12.3%）和中性粒细胞减少（8.8%）。报告了4例因严重不良事件导致的死亡，这些事件被认为与研究药物无关。
LAN联合TMZ是进展期GEP-NET患者的一种治疗选择，这类患者具有更具侵袭性的生物学特征，但安全性可控。
