Liposomal Irinotecan Plus 5-FU/LV Improves Survival Outcomes in Biliary Tract Cancer


Liposomal irinotecan (Onivyde) plus 5-fluorouracil/leucovorin (5-FU/LV) mproved progression-free survival (PFS) and overall survival (OS) in patients with metastatic biliary tract cancer whose disease had progressed after frontline gemcitabine/cisplatin.

Liposomal irinotecan (Onivyde) plus 5-fluorouracil/leucovorin (5-FU/LV) mproved progression-free survival (PFS) and overall survival (OS) in patients with metastatic biliary tract cancer whose disease had progressed after frontline gemcitabine/cisplatin, according to data from the phase 2 NIFTY trial (NCT03524508), which was presented at the 2021 ASCO Annual Meeting.

At a median follow-up of 11.8 months, the median PFS for patients treated with liposomal irinotecan plus 5-FU/LV (n = 88) was 7.1 months (95% CI, 3.6-8.8) compared with 1.4 months (95% CI, 1.2-1.5) for patients treated with 5-FU/LV alone (n = 86). These data correspond with a 44% reduction in the risk of progression (HR, 0.56; 95% CI, 0.39-0.81; P = .0019). The median OS was 8.6 months (95% CI, 5.4-10.5) and 5.5 months (95% CI, 4.7-7.2), respectively (HR, 0.68; 95% CI, 0.48-0.98; P = 0.349).

“[Liposomal irinotecan] plus 5-FU/LV should be considered as one of the standard treatments for patients with advanced biliary tract cancer [whose disease has progressed] on gemcitabine/cisplatin,” Changhoon Yoo, MD, PhD, said in a presentation of the data. Yoo added that benefit was observed in the “preplanned subgroup analysis for blind independent central review–assessed PFS, investigator review–assessed PFS, and OS, all [of which] favored the liposomal irinotecan plus 5-FU/LV reporting group and there was no significant interaction.”

Yoo is an assistant professor of oncology at the University of Ulsan College of Medicine and Asan Medical Center in Seoul, Korea.

Liposomal irinotecan is a topoisomerase inhibitor that contains SN-38, an active metabolite of irinotecan that binds reversibly to the topoisomerase 1-DNA complex and prevents religation of the single strand breaks.2 The agent is approved for the treatment of patients with gemcitabine -refractory metastatic pancreatic cancer based on data from the phase 3 NAPOLI-1 trial (NCT01494506).2

Investigators hypothesized that liposomal irinotecan would elicit similar response in patients with biliary tract cancer because of biologic similarities in the tumor stroma. The randomized phase 2 NIFTY trial enrolled patients with metastatic biliary tract cancer with a least 1 measurable lesion per RECIST v1.1. Patients also had to have confirmed radiological progression following first-line gemcitabine/cisplatin, no prior treatment with second-line chemotherapy, adequate organ function, and an ECOG performance status of 0 to 1.1

Patients were stratified by tumor site—intrahepatic vs extrahepatic/gallbladder—prior surgery with curative intent, and by their participating treatment center. In total 174 patients were randomized to receive liposomal irinotecan 70 mg/m2 on day 1 plus 5-FU (2400 mg/m2) on days 1-2 plus LV (400 mg/m2 on day 1 every 2 weeks or 5-FU/LV every 2 weeks until disease progression per investigator review or intolerable toxicities.

The primary end point is PFS by blind independent review committee (BICR). Secondary end points include investigator-assessed PFS, OS, overall response rate (ORR), quality of life assessed by EORTC QLQ-C30 and safety. Radiological tumor assessment by CT or MRI was completed every 6 weeks from day 1 of cycle 1.

The treatment arms were well balanced; the median age in the liposomal irinotecan plus 5-FU/LV arm was 63 years (range, 38-84) and 65 years (range, 37-80) in the 5-FU/LV alone arm. Intrahepatic carcinoma was most common across the groups (39.8% vs 45.3%, respectively), followed by gallbladder (35.2% vs 25.6%) and extrahepatic carcinoma (25.0% vs 29.1%). The median duration of first-line gemcitabine was 5.1 months and most patients had not undergone prior curative-intent surgery, 70.5% and 66.3%, respectively.

Additional PFS data from the BICR–assessed review showed a 6-month PFS rate of 55.7% (95% CI, 44.7%-66.6%) for those in the liposomal irinotecan plus 5-FU/LV arm compared with 26.2% (95% CI, 16.6%-35.8%) in the 5-FU/LV arm.

Investigator-assessed PFS data demonstrated similar efficacy outcomes favoring the addition of liposomal irinotecan. The median PFS in the combination arm was 3.9 months (95% CI, 2.7-5.2) compared with 1.6 months (95% CI, 1.3-2.2) in the 5-FU/LV arm (HR, 0.48; 95% CI, 0.34-0.69; P < .0001). The 6-month PFS rates were 30.6% (95% CI, 20.6%-40.5%) and 11.6% (4.9%-18.4%), respectively.

OS rates were also reported for both regimens. The 6-month OS rate for the liposomal irinotecan arm was 60.7% (95% CI, 50.3%-71.2%) compared with 45.9% (35.3%-56.5%) in the 5-FU/LV arm. The 1-year OS rates were 35.4% (95% CI, 24.9%-45.9%) and 22.4% (95% CI, 13.1%-31.7%), respectively.

Liposomal irinotecan plus 5-FU/LV elicited an ORR of 14.8% compared with 5.8% with 5-FU/LV alone as assessed by BICR (P = .0684). Half of patient in the liposomal irinotecan arm had stable disease and 14.8% had a partial response vs 29.1% and 5.8%, respectively, in the 5-FU/LV arm. More than half of patients in the 5-FU/LV arm had progressive disease (64.0%) vs 29.5% in the liposomal irinotecan arm. No complete responses were reported in either arm. Investigator-assessed review reported similar results.

“The safety profile for liposomal irinotecan plus 5-FU/LV was consistent with that seen in the previous NAPOLI-1 trial for pancreatic cancer,” Yoo explained. “Neutropenia and fatigue were the most commonly observed any-grade and grade 3 and 4 adverse events for the liposomal irinotecan plus 5-FU/LV group,” he said.

Specifically, neutropenia of any grade was reported in 33.0% of patients in the liposomal irinotecan plus 5-FU/LV arm vs 3.5% in the 5-FU/LV arm. Incidence rates of grade 3 or 4 neutropenia were 23.9% and 1.2% in the arms, respectively. Incidence of any grade fatigue was reported in 30.7% of patients in the liposomal irinotecan arm compared with 19.8% in the 5-FU/LV arm; grade 3 or 4 incidence rates were 12.5% vs 3.5%, respectively.

“We assessed patient-reported quality of life using the EORTC QLQ-C30 questionnaire measured over 8 cycles of the study treatment,” Yoo said. “Overall quality of life was well-preserved in both arms and there were no clinically meaningful differences in global health–related quality of life in the arms.”

Finally, 34.9% of patients in the liposomal irinotecan plus 5-FU/LV arm went on to receive post study treatment and the most common therapy was fluoropyrimidine plus cisplatin or oxaliplatin (17.4%). In the 5-FU/LV arm, 31.8% of patients went on to receive post treatment therapy, the most common of which was pembrolizumab (Keytruda; 11.8%).

Yoo concluded by noting that the despite the fact that the study was conducted in Korea only, the study was appropriately powered to compare 2 treatment groups and was designed for meticulous tumor response evaluation and that the combination should be considered as a treatment option for patients with biliary tract cancer in the second line.


  1. Yoo C, Kim KP, Kim I, et al. Liposomal irinotecan (nal-IRI) in combination with fluorouracil (5-FU) and leucovorin (LV) for patients with metastatic biliary tract cancer (BTC) after progression on gemcitabine plus cisplatin (GemCis): multicenter comparative randomized phase 2b study (NIFTY). J Clin Oncol. 2021;39(suppl 15):4006. doi:10.1200/JCO.2021.39.15_suppl.4006
  2. Onivyde. Prescribing information. Merrimack Pharmaceuticals Inc. Accessed June 5, 2021.
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