Background: 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. Methods: 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/m2and leucovorin 400 mg/m2, followed by 5-FU 2400 mg/m2biweekly 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. Results: 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 (p= 0.005 andp= 0.013, respectively). UGT1A1*28 polymorphism was not associated with OS, PFS, or toxicity. Conclusion: 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.
背景：神经内分泌癌（NEC）的一线治疗采用铂类联合依托泊苷方案，目前尚无标准二线疗法。本研究探索了纳米脂质体伊立替康（Nal-IRI）联合5-氟尿嘧啶（5-FU）及亚叶酸（LV）在晚期难治性NEC中的疗效，并探讨了UGT1A1*28多态性对治疗结果和毒性的影响。 方法：本研究为开放标签、单臂、多中心II期临床试验，纳入经一线治疗后进展或不耐受的胃肠胰（GEP）或原发灶不明的晚期NEC患者。符合条件患者每两周接受Nal-IRI（70 mg/m²）联合LV（400 mg/m²）及5-FU（2400 mg/m²）治疗，直至疾病进展或出现不可耐受毒性。主要终点为客观缓解率（ORR），次要终点包括无进展生存期（PFS）、总生存期（OS）及毒性反应。在基线和治疗期间对血液/组织样本进行二代测序（NGS）。 结果：共入组11例患者，其中9例可评估主要终点。男性7例，中位年龄66.7岁，中位Ki-67指数为90%。观察到1例部分缓解，6例疾病稳定，2例疾病进展。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）。最常见不良事件为腹泻（45%）、恶心（45%）、呕吐（45%）和疲劳（45%）。NGS检测显示最常见基因突变为TP53（88.9%）、CHEK2（88.9%）和APC（33.3%）。携带CHEK2与APC突变患者PFS显著延长（分别为p=0.005和p=0.013）。UGT1A1*28多态性与OS、PFS或毒性无显著相关性。 结论：Nal-IRI联合5-FU/LV是治疗GEP或原发灶不明难治性高级别NEC的安全有效方案。未来研究应探索Nal-IRI在高级别NEC一线及难治性治疗中的新型联合方案。
肿瘤(癌症)患者之家