背景：在 BTC 的 GemCI 進展之後，還沒有全球公認的二線治療方法。雖然 ABC-06 試驗表明，與主動症狀控製相比，mFOLFOX 有臨床獲益，但仍需進一步研究。

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 是一項由研究人員發起的、多中心、開放、隨機的 2b 期研究。年齡>19 歲、ECOG PS 為 0/1、組織學證實有轉移的 BTC 和一線 GemCI 疾病進展的 PTS 符合條件。PTS 隨機分為 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。根據 RECIST V1.1，每 6 周(固定時間表)評估腫瘤反應。主要終點是每項盲法獨立中心評價(BICR)的無進展生存期(PFS)。次要終點是每位研究員回顧的 PFS、總存活率(OS)、總應答率(ORR)和安全性。本研究旨在將中位 PFS 從 2 個月(P0)提高到 3.3 個月(P1； HR 0.6)，雙側α值為 0.05，功率為 80%，隨訪率為 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.

結果：自 2018 年 2 月至 2020 年 2 月共納入 178 例 SEP 患者，排除 4 例未接受任何研究治療的患者，174 例納入完全分析集(NAL-IRI+5-FU/LV 組 88 例，5-FU/LV 組 86 例)。中位年齡 64 歲(37-84 歲)，男/女 99/75 例，肝內/肝外/膽囊癌 74/47/53 例。PTS 特征在兩組間平衡良好。 Nal-IRI+5-FU/LV 組和 5-FU/LV 組的中位隨訪時間分別為 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)；每個調查 者 回 顧 的 中 位 PFS 分 別 為 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 分別為 8.6mo(5.4~10.5) 和 5.5mo(4.7~7.2mo)(HR=0.6 8[0.48~0.98]，p=0.0349)。每個 BICR 的 ORR 分別為 14.8% 和 5.8%(p=0.0684)，每個研究者綜述的 ORR 分別為 19.3%和 2.3%(p=0.0002)。NAL-IRI 加 5-FU/LV 組 68 例 (77.3%) 和 5-FU/LV 組 27 例 (31.4%) 發生 3 級不良事件 (AEs) 。 NAL-IRI+5-FU/LV 組最常見的 3 級不良反應為中性粒細胞減少(n=21，23.9%)、乏力(7，8.0%)和惡心(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%).

結論：與之前 GemCI 進展的 BTC 患者相比，NalIRI 加 5-FU/LV 顯著改善了 PFS 和 OS。NAL-IRI聯合 5-FU/LV 可作為晚期 BTC 的標準二線治療方案。

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.