Liposomal Irinotecan in Combination with Fluorouracil and Leucovorin Versus Fluorouracil and Leucovorin for Metastatic Biliary Tract Cancer after Progression on Gemcitabine Plus Cisplatin (NIFTY): A Multicentre, Open-Label, Comparative, Randomised Phase 2b Study

Background: Gemcitabine plus cisplatin is the standard first-line therapy for advanced biliary tract cancer, and the prognosis of patients who progress on gemcitabine plus cisplatin is poor. We aimed to determine the benefit of the addition of liposomal irinotecan (nal-IRI) to second-line fluorouracil and leucovorin (5-FU/LV) in advanced biliary tract cancer. Methods: The NIFTY trial is a multicentre, open-label, randomised, comparative, phase 2b study carried out in five tertiary referral centres in South Korea. Adult patients (age > 19 years) with histologically or cytologically confirmed biliary tract cancer, documented radiological disease progression on first-line gemcitabine and cisplatin, metastatic disease, and ECOG performance status of 0-1 were randomly assigned in a 1:1 ratio to nal-IRI (70 mg/m2, 90 min) plus 5-FU (2400 mg/m2, 46 hours)/LV (400 mg/m2, 30 min) or 5-FU/LV, every 2 weeks. Randomisation was stratified per primary tumor sites, prior curative surgery, and participating centre. The primary endpoint is progression-free survival (PFS) per blinded independent central review (BICR). Secondary endpoints are PFS per investigator review, overall survival (OS), overall response rate, and safety profile. This trial is registered with ClinicalTrials.gov (NCT03524508). Findings: Between September 5, 2018 and February 18, 2020, 174 patients were randomly assigned and included in the full analysis set (88 for the nal-IRI plus 5-FU/LV group and 86 for the 5-FU/LV group). At a median follow-up of 11·8 months [IQR, 7·7–18·7], the nal-IRI+5-FU/LV group had a significantly longer median PFS per BICR (7·1 months [95% CI 3.6-8.8] vs 1·4 months [95% CI 1.2-1.5]; HR 0·56 [95% CI 0·39–0·81], p=0·0019), and median OS (8·6 [95% CI 5.4–10.5] vs 5·5 months [95% CI 4.7–7.2]; HR 0·68 [0·48–0·98], p=0·0349) than did the 5-FU/LV group. Grade≥ 3 adverse events were reported in 77·3% of the nal-IRI plus 5-FU/LV group and 31·4% of the 5-FU/LV group. Interpretation: Addition of nal-IRI to 5-FU/LV significantly improved PFS and OS in patients with advanced biliary tract cancer who progressed on first-line gemcitabine plus cisplatin. Nal-IRI plus 5-FU/LV may be regarded as one of the standard second-line regimens for advanced biliary tract cancer. Further investigation in the global patient population with OS as a primary endpoint may be needed to validate the current findings. Funding: Servier and HK inno.N Declaration of Interests: CY has received honoraria from Servier, Bayer, AstraZeneca, Merck Sharp & Dohme, Eisai, Celgene, Bristol-Myers Squibb, Debiopharm, Ipsen, Kyowa Kirin, Novartis, Boryung Pharmaceuticals, Merck Serono, Mundipharma, Roche, and Janssen, and has received research grants from Servier, Bayer, AstraZeneca, Ono Pharmaceuticals, Celgene, Ipsen, Boryung Pharmaceuticals, Ildong Pharmaceuticals, CKD Pharmaceuticals, and HK. inno.N. JHJ has received honoraria from Boryung Pharmaceutical, Daewoong Pharmaceutical, Eisai, HK. inno.N, Lilly, Novartis, Pfizer, and Roche. JC has received honoraria from Roche, Bayer, Eisai, Ipsen, Bristol-Myers Squibb and has received research grants from Bayer and Dong-A Pharmaceuticals. GKA-A reports research grants and personal fees for consulting from Incyte Corporation; research grants and personal fees for consulting from Agios, AstraZeneca, Bayer, Beigene, Bristol-Myers Squibb, Celgene, Exelixis, Polaris, and QED; research grants from Array, ActaBiologica, Genentech, CASI, Mabvax, Halozyme, Novartis, OncoQuest, Puma Biotechnology, and Roche; and personal fees for consulting from Autem, Berry Gemomics, Bioline, CytomX, Debiopharm, Eisai, Eli Lilly, Flatiron, Genoscience, Ipsen, Jansen, LAM, Loxo, Merck, MINA, Pfizer, RedHill, Silenseed, Sillajen, Sobi, Targovax, Therabionics, Twoxar, and Yiviva. KpK, IK, MJK, BWK, HR, JSL, KK, and BYR declare no competing interests Ethics Approval Statement: The study protocol was approved by the institutional review board of each participating centre. All patients provided written informed consent before enrolment. Trial Registration: This trial is registered with ClinicalTrials.gov (NCT03524508).