Mukherjee Sarbajit, Pattnaik Harsha, Sonti Sahithi, Ramesh Mrinalini, Jain Prantesh, Ramirez Robert A, Fountzilas Christos, Vadehra Deepak, Attwood Kristopher, Iyer Renuka
Roswell Park Comprehensive Cancer Center, Buffalo, NY 14203, USA.
Department of Internal Medicine, University at Buffalo, Buffalo, NY 14203, USA.
Cancers (Basel). 2025 Jan 12;17(2):224. doi: 10.3390/cancers17020224.
Neuroendocrine carcinomas (NECs) are treated with a frontline platinum-etoposide combination with no standard second-line therapies. We explored a novel combination of nanoliposomal irinotecan (Nal-IRI), 5-fluorouracil (5-FU), and leucovorin (LV) in advanced refractory NECs and investigated the impact of UGT1A1*28 polymorphism on treatment outcomes and toxicity.
We conducted an open-label, single-arm, multi-center Phase 2 trial in advanced NEC patients of gastroenteropancreatic (GEP) or unknown origin with progression or intolerance to first-line therapy. Eligible patients received nal-IRI 70 mg/m and leucovorin 400 mg/m, followed by 5-FU 2400 mg/m biweekly till disease progression or unacceptable toxicity. The primary endpoint was the objective response rate (ORR). Secondary endpoints included progression-free survival (PFS), overall survival (OS), and toxicity. Next-generation sequencing (NGS) was performed on blood/tissue samples at baseline and during treatment.
Eleven patients were enrolled, with nine evaluable for the primary endpoint. Seven were male, the median age was 66.7 years, and the median Ki-67 was 90%. We observed partial response in one patient, stable disease in six patients, and progressive disease in two patients. The median OS was 9.4 months (95% CI 2.9-29.3), and the median PFS was 4.4 months (95% CI 1.7-6.7). The most common adverse events were diarrhea (45%), nausea (45%), vomiting (45%), and fatigue (45%). The most common genetic mutations on NGS were TP53 (88.9%), CHEK2 (88.9%), and APC (33.3%). Patients with CHEK2 and APC mutation had longer PFS ( = 0.005 and = 0.013, respectively). UGT1A1*28 polymorphism was not associated with OS, PFS, or toxicity.
Nal-IRI with 5-FU/LV is a safe and effective treatment for refractory high-grade NECs of GEP or unknown origin. Future studies should explore novel combinations with Nal-IRI in high-grade NECs both in frontline and refractory settings.
神经内分泌癌（NECs）的一线治疗采用铂类-依托泊苷联合方案，尚无标准的二线治疗方法。我们探索了纳米脂质体伊立替康（Nal-IRI）、5-氟尿嘧啶（5-FU）和亚叶酸钙（LV）在晚期难治性NECs中的新型联合方案，并研究了UGT1A1*28基因多态性对治疗效果和毒性的影响。
我们对一线治疗进展或不耐受的胃肠胰（GEP）来源或来源不明的晚期NEC患者进行了一项开放标签、单臂、多中心2期试验。符合条件的患者接受Nal-IRI 70mg/m²和亚叶酸钙400mg/m²，随后每两周接受5-FU 2400mg/m²，直至疾病进展或出现不可接受的毒性。主要终点是客观缓解率（ORR）。次要终点包括无进展生存期（PFS）、总生存期（OS）和毒性。在基线和治疗期间对血液/组织样本进行二代测序（NGS）。
共纳入11例患者，9例可评估主要终点。7例为男性，中位年龄为66.7岁，中位Ki-67为90%。我们观察到1例患者部分缓解，6例患者疾病稳定，2例患者疾病进展。中位OS为9.4个月（95%CI 2.9-29.3），中位PFS为4.4个月（95%CI 1.7-6.7）。最常见的不良事件为腹泻（45%）、恶心（45%）、呕吐（45%）和疲劳（45%）。NGS上最常见的基因突变是TP53（88.9%）、CHEK2（88.9%）和APC（33.3%）。CHEK2和APC突变的患者PFS更长（分别为P=0.005和P=0.013）。UGT1A1*28基因多态性与OS、PFS或毒性无关。
Nal-IRI联合5-FU/LV是治疗GEP来源或来源不明的难治性高级别NECs的一种安全有效的方法。未来的研究应探索在一线和难治性情况下Nal-IRI与高级别NECs的新型联合方案。
