背景：在 BTC 的 GemCI 进展之后，还没有全球公认的二线治疗方法。虽然 ABC-06 试验表明，与主动症状控制相比，mFOLFOX 有临床获益，但仍需进一步研究。

Background: There is no globally established second-line therapy after progression on GemCis in BTC. Although ABC-06 trial showed the clinical benefit of mFOLFOX compared to active symptom control, further investigation is needed.

方法：Nifty 是一项由研究人员发起的、多中心、开放、随机的 2b 期研究。年龄>19 岁、ECOG PS 为 0/1、组织学证实有转移的 BTC 和一线 GemCI 疾病进展的 PTS 符合条件。PTS 随机分为 Nal-IRI(70 mg/m2，90min)+5-FU(2400 mg/m2，46h)/LV(400 mg/m2，30min)，每 2 周或 5-FU/LV，每 2 周一次。根据 RECIST V1.1，每 6 周(固定时间表)评估肿瘤反应。主要终点是每项盲法独立中心评价(BICR)的无进展生存期(PFS)。次要终点是每位研究员回顾的 PFS、总存活率(OS)、总应答率(ORR)和安全性。本研究旨在将中位 PFS 从 2 个月(P0)提高到 3.3 个月(P1； HR 0.6)，双侧α值为 0.05，功率为 80%，随访率为 10%，共 174 例患者。

Methods: NIFTY is an investigator-initiated, multicenter, open-label, randomized, phase 2b study. Pts with > 19 years, ECOG PS 0/1, histologically confirmed metastatic BTC, and disease progression on first-line GemCis were eligible. Pts were randomized 1:1 to nal-IRI (70 mg/m2, 90 min) plus 5-FU (2400 mg/m2, 46 hours)/LV (400 mg/m2, 30 min), every 2 weeks or 5-FU/LV, every 2 weeks until disease progression per investigator review or intolerable toxicities (stratification: primary tumor site, prior surgery and institution). Tumor response was evaluated per RECIST v1.1, every 6 weeks (fixed schedule). Primary endpoint is progression-free survival (PFS) per blinded independent central review (BICR). Secondary endpoints were PFS per investigator review, overall survival (OS) overall response rates (ORR), and safety. This study was designed to improve median PFS from 2 months (P0) to 3.3 months (P1; HR 0.6) with 2-sided alpha of 0.05, power of 80% and follow-up loss rates of 10%; a total of 174 pts were required.

结果：自 2018 年 2 月至 2020 年 2 月共纳入 178 例 SEP 患者，排除 4 例未接受任何研究治疗的患者，174 例纳入完全分析集(NAL-IRI+5-FU/LV 组 88 例，5-FU/LV 组 86 例)。中位年龄 64 岁(37-84 岁)，男/女 99/75 例，肝内/肝外/胆囊癌 74/47/53 例。PTS 特征在两组间平衡良好。 Nal-IRI+5-FU/LV 组和 5-FU/LV 组的中位随访时间分别为 6.1mo(IQR3.5~11.2mo) 和7.1mo(95%CI，3.68.8)和 1.4mo(1.2mo~1.5mo)(HR=0.56[0.39~0.81]，p=0.0019)；每个调查 者 回 顾 的 中 位 PFS 分 别 为 3.9mo(2.7mo~5.2mo) 和1.6mo(1.3mo~2.2mo)(HR=0.48[0.340.69]，P<0.0001)。中位 OS 分别为 8.6mo(5.4~10.5) 和 5.5mo(4.7~7.2mo)(HR=0.6 8[0.48~0.98]，p=0.0349)。每个 BICR 的 ORR 分别为 14.8% 和 5.8%(p=0.0684)，每个研究者综述的 ORR 分别为 19.3%和 2.3%(p=0.0002)。NAL-IRI 加 5-FU/LV 组 68 例 (77.3%) 和 5-FU/LV 组 27 例 (31.4%) 发生 3 级不良事件 (AEs) 。 NAL-IRI+5-FU/LV 组最常见的 3 级不良反应为中性粒细胞减少(n=21，23.9%)、乏力(7，8.0%)和恶心(5，5.7%)。

Results: A total of 178 patients were enrolled between SEP 2018 and FEB 2020; with exclusion of 4 pts who did not receive any study treatment, 174 pts (88 for nal-IRI plus 5-FU/LV group and 86 for 5-FU/LV group) were included in the Full Analysis Set. Median age was 64 yrs (range 37-84); 99/75 pts were male/female; 74/47/53 pts had intrahepatic/extrahepatic/gallbladder cancers. Pts characteristics were well balanced between two arms. With median follow-up duration of 6.1 mo (IQR 3.5-11.2), median PFS per BICR in nal-IRI plus 5-FU/LV group and 5-FU/LV group was 7.1 mo (95% CI, 3.6-8.8) and 1.4 mo (1.2-1.5), respectively (HR=0.56 [0.39-0.81], p=0.0019); median PFS per investigator review was 3.9 mo (2.7-5.2) and 1.6 mo (1.3-2.2), respectively (HR=0.48 [0.34-0.69], p<0.0001). Median OS was 8.6 mo (5.4-10.5) and 5.5 mo (4.7-7.2), respectively (HR=0.68 [0.48-0.98], p=0.0349). ORR was 14.8% and 5.8% per BICR, respectively (p=0.0684) and 19.3% and 2.3% per investigator review, respectively (p=0.0002). Grade ≥3 adverse events (AEs) were reported in 68 pts (77.3%) of nal-IRI plus 5-FU/LV group and 27 pts (31.4%) of 5-FU/LV group. Most common grade ≥3 AEs in nal-IRI plus 5-FU/LV group were neutropenia (n=21, 23.9%), fatigue (7, 8.0%), and nausea (5, 5.7%).

结论：与之前 GemCI 进展的 BTC 患者相比，NalIRI 加 5-FU/LV 显著改善了 PFS 和 OS。NAL-IRI联合 5-FU/LV 可作为晚期 BTC 的标准二线治疗方案。

Conclusion: Nal-IRI plus 5-FU/LV significantly improved PFS and OS compared to 5-FU/LV in BTC pts who progressed on prior GemCis. Nal-IRI plus 5-FU/LV should be considered as standard second-line therapy for advanced BTC.