Liposomal irinotecan plus fluorouracil and leucovorin versus fluorouracil and leucovorin for metastatic biliary tract cancer after progression on gemcitabine plus cisplatin (NIFTY): a multicentre, open-label, randomised, phase 2b study,The Lancet Oncology

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Liposomal irinotecan plus fluorouracil and leucovorin versus fluorouracil and leucovorin for metastatic biliary tract cancer after progression on gemcitabine plus cisplatin (NIFTY): a multicentre, open-label, randomised, phase 2b study
The Lancet Oncology ( IF 51.1 ) Pub Date : 2021-10-14 , DOI: 10.1016/s1470-2045(21)00486-1
Changhoon Yoo ₁ , Kyu-Pyo Kim ₁ , Jae Ho Jeong ₁ , Ilhwan Kim ₂ , Myoung Joo Kang ₂ , Jaekyung Cheon ₃ , Byung Woog Kang ₄ , Hyewon Ryu ₅ , Ji Sung Lee ₆ , Kyung Won Kim ₇ , Ghassan K Abou-Alfa ₈ , Baek-Yeol Ryoo ₁

Affiliation

Department of Oncology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, South Korea.
Division of Oncology, Department of Internal Medicine, Haeundae Paik Hospital, Inje University College of Medicine, Busan, South Korea.
Division of Hematology and Oncology, Department of Internal Medicine, Ulsan University Hospital, University of Ulsan College of Medicine, Seoul, South Korea.
Department of Oncology/Hematology, Kyungpook National University Hospital, Kyungpook National University, Daegu, South Korea.
Division of Hematology and Oncology, Department of Internal Medicine, Chungnam National University Hospital, Chungnam National University College of Medicine, Daejeon, South Korea.
Clinical Research Center, Asan Institute for Life Sciences, University of Ulsan College of Medicine, Seoul, South Korea; Department of Clinical Epidemiology and Biostatistics, University of Ulsan College of Medicine, Seoul, South Korea.
Asan Image Metrics, Clinical Research Center, Asan Institute for Life Sciences, University of Ulsan College of Medicine, Seoul, South Korea.
Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY, USA; Department of Medicine, Weill Medical College at Cornell University, New York, NY, USA.

Background

The prognosis of patients with advanced biliary tract cancer who have progressed on gemcitabine plus cisplatin is dismal. We aimed to investigate the efficacy and safety of second-line liposomal irinotecan plus fluorouracil and leucovorin in patients with metastatic biliary tract cancer that has progressed on gemcitabine plus cisplatin.

Methods

This multicentre, open-label, randomised, phase 2b (NIFTY) study was done at five academic institutions in South Korea and included patients aged 19 years or older with histologically or cytologically confirmed metastatic biliary tract cancer that had progressed on first-line gemcitabine plus cisplatin and an Eastern Cooperative Oncology Group performance status of 0 or 1. By use of an interactive web-based response system integrated with an electronic data capture system, patients were randomly assigned (1:1) using permuted blocks (block size 4) to receive either intravenous liposomal irinotecan (70 mg/m² for 90 min) plus intravenous leucovorin (400 mg/m² for 30 min) and intravenous fluorouracil (2400 mg/m² for 46 h) every 2 weeks or leucovorin and fluorouracil only every 2 weeks, and were stratified by primary tumour site, previous surgery with curative intent, and participating centre. Study treatment was continued until the patient had disease progression or unacceptable toxicities, or withdrew consent. The primary endpoint was blinded independent central review (BICR)-assessed progression-free survival. The primary endpoint and safety were assessed in the full analysis set and the safety analysis set, respectively, both of which comprised all randomly assigned patients who received at least one dose of the study treatment. This trial is registered with ClinicalTrials.gov, NCT03524508, and enrolment is complete.

Findings

Between Sept 5, 2018, and Feb 18, 2020, 193 patients were screened for eligibility, of whom 174 (88 in the liposomal irinotecan plus fluorouracil and leucovorin group and 86 in the fluorouracil plus leucovorin group) were enrolled and included in the full analysis and safety analysis sets. At a median follow-up of 11·8 months (IQR 7·7–18·7), the median BICR-assessed progression-free survival was significantly longer in the liposomal irinotecan plus fluorouracil and leucovorin group (7·1 months, 95% CI 3·6–8·8) than in the fluorouracil and leucovorin group (1·4 months, 1·2–1·5; hazard ratio 0·56, 95% CI 0·39–0·81; p=0·0019). The most common grade 3–4 adverse events were neutropenia (21 [24%] of 88 in the liposomal irinotecan plus fluorouracil and leucovorin group vs one [1%] of 86 in the fluorouracil and leucovorin group) and fatigue or asthenia (11 [13%] vs three [3%]). Serious adverse events occurred in 37 (42%) patients receiving liposomal irinotecan plus fluorouracil and leucovorin and 21 (24%) patients receiving fluorouracil and leucovorin. There were no treatment-related deaths.

Interpretation

Adding liposomal irinotecan to fluorouracil and leucovorin significantly improved BICR-assessed progression-free survival in patients with advanced biliary tract cancer. Liposomal irinotecan plus fluorouracil and leucovorin could be considered a standard-of-care second-line therapy for advanced biliary tract cancer.