Sahai Vaibhav, Griffith Kent A, Lin Bruce S, Soares Heloisa P, Chandana Sreenivasa R, Crysler Oxana, Kumar-Sinha Chandan, Enzler Thomas, Dippman Dominique, Gunchick Valerie, Zalupski Mark M
Division of Hematology and Oncology, Department of Internal Medicine, University of Michigan, Ann Arbor, MI, USA; Rogel Cancer Center, University of Michigan, Ann Arbor, MI, USA.
Center for Cancer Biostatistics, University of Michigan School of Public Health, Ann Arbor, MI, USA.
Med. 2025 Apr 11;6(4):100547. doi: 10.1016/j.medj.2024.10.024. Epub 2024 Dec 18.
Second-line chemotherapy with 5-fluorouracil/leucovorin (5FULV) and liposomal irinotecan improves survival in advanced biliary tract cancer (BTC). In this phase 1b/2 trial, we investigated the combination of 5FULV and liposomal irinotecan with nivolumab following progression on first-line chemotherapy for advanced BTC.
Patients received 2,400 mg/m 5-fluorouracil, leucovorin (dose level: 0:400 or -1:200 mg/m), 70 mg/m liposomal irinotecan, and 240 mg nivolumab every 2 weeks (ClinicalTrials.gov: NCT03785873). The phase 1b and 2 primary objectives included recommended phase 2 dose (RP2D) and median progression-free survival (PFS; null and alternative hypotheses of 2.9 and 5.0 months) with a two-sided alpha of 0.05 and >80% power. Secondary objectives were safety, objective response rate (ORR), and overall survival (OS).
Of 30 patients with a median age of 63.5 years, 18 (60%) were men, 25 (83%) were White, 16 (53%) had an ECOG performance status of 0, and 19 (63.3%) had intrahepatic cholangiocarcinoma. In phase 1b, the RP2D was dose level 0 after a dose-limiting toxicity event of enterocolitis (n = 1). Median PFS was 4.1 months (95% confidence interval [CI], 1.9-9.9). The ORR was 16.7% (5 partial responses) per irRECIST, the median OS was 7.4 months (95% CI, 5.7-15.9), and the 24-month survival rate was 23.3%. The most common grade ≥3 treatment-related adverse events were diarrhea (5; 16.7%), fatigue (4; 13.3%), and neutropenia (3; 10%).
Treatment was well tolerated, but the primary endpoint was not met. The median OS was similar to prior trials with this drug combination, but the 24-month survival rate was higher than expected.
This work was funded by Ipsen Biopharmaceuticals, Bristol-Myers Squibb (CA209-8LF), and the University of Michigan Rogel Cancer Center (P30CA046592).
5-氟尿嘧啶/亚叶酸钙（5FULV）联合脂质体伊立替康的二线化疗可改善晚期胆管癌（BTC）患者的生存率。在这项1b/2期试验中，我们研究了晚期BTC患者一线化疗进展后，5FULV联合脂质体伊立替康与纳武单抗的联合治疗效果。
患者每2周接受2400mg/m²的5-氟尿嘧啶、亚叶酸钙（剂量水平：0:400或-1:200mg/m²）、70mg/m²的脂质体伊立替康和240mg纳武单抗（ClinicalTrials.gov：NCT03785873）。1b期和2期的主要目标包括确定2期推荐剂量（RP2D）和中位无进展生存期（PFS；原假设和备择假设分别为2.9个月和5.0个月），双侧α为0.05，检验效能>80%。次要目标包括安全性、客观缓解率（ORR）和总生存期（OS）。
30例患者的中位年龄为63.5岁，其中18例（60%）为男性，25例（83%）为白人，16例（53%）的东部肿瘤协作组（ECOG）体能状态为0，19例（63.3%）患有肝内胆管癌。在1b期，因1例发生小肠结肠炎的剂量限制性毒性事件，RP2D为剂量水平0。中位PFS为4.1个月（95%置信区间[CI]，1.9 - 9.9）。根据irRECIST标准，ORR为16.7%（5例部分缓解），中位OS为7.4个月（95%CI，5.7 - 15.9），24个月生存率为23.3%。最常见的≥3级治疗相关不良事件为腹泻（5例；16.7%）、疲劳（4例；13.3%）和中性粒细胞减少（3例；10%）。
治疗耐受性良好，但未达到主要终点。中位OS与此前该药物联合方案的试验相似，但24个月生存率高于预期。
本研究由益普生生物制药公司、百时美施贵宝（CA209 - 8LF）以及密歇根大学罗格尔癌症中心（P30CA046592）资助。
