
==== Front
J Clin Oncol
J Clin Oncol
jco
JCO
Journal of Clinical Oncology
0732-183X
1527-7755
Wolters Kluwer Health

38843469
JCO.23.01566
10.1200/JCO.23.01566
ORIGINAL REPORTS
Gastrointestinal Cancer
Nanoliposomal Irinotecan With Fluorouracil and Leucovorin or Gemcitabine Plus Cisplatin in Advanced Cholangiocarcinoma: A Phase II Study of the AIO Hepatobiliary-YMO Cancer Groups (NIFE-AIO-YMO HEP-0315)
https://orcid.org/0000-0002-7654-2442
Ettrich Thomas J. MD 1
https://orcid.org/0000-0002-6853-0599
Modest Dominik P. MD 2
https://orcid.org/0000-0002-7155-1278
Sinn Marianne MD 3
Striefler Jana K. MD 2
Opitz Bernhard MD 4
Goetze Thorsten MD 5
Gallmeier Eike MD 6
Angermeier Stefan MD 7
Fischer von Weikersthal Ludwig MD 8
Jacobasch Lutz MD 9
Waldschmidt Dirk MD 10
Niedermeier Michael MD 11
Sohm Michael MD 12
Berger Andreas W. MD 1
https://orcid.org/0000-0002-8032-8043
Manzini Giulia MD 13
Fehrenbach Uli MD 14
Auer Timo Alexander MD 14
https://orcid.org/0000-0002-4383-5716
Hosse Clarissa MD 14
Vogele Daniel MD 15
Sookthai Disorn MSc 16
Schaaf Marina MSc 16
Muche Rainer PhD 17
https://orcid.org/0000-0002-6037-8836
Hinke Axel PhD 18
Seufferlein Thomas MD 1
https://orcid.org/0000-0003-0484-0974
Perkhofer Lukas MD 1 19
1 Department of Internal Medicine I, University of Ulm, Ulm, Germany
2 Hematology, Oncology and Tumor Immunology, Charité—Universitätsmedizin Berlin, Berlin, Germany
3 Department of Oncology, Hematology and BMT with Division of Pneumology, University Hospital Hamburg-Eppendorf, Hamburg, Germany
4 Department of Hematology and Oncology, Hospital St Elisabeth and St Barbara Halle, Halle, Germany
5 Institute of Clinical Cancer Research (IKF) at Northwest Hospital, UCT-University Cancer Center, Frankfurt Am Main, Germany
6 Department of Gastroenterology and Endocrinology, Philipps University Marburg, Marburg, Germany
7 Department of Gastroenterology and Hematology and Oncology, Ludwigsburg Hospital, Ludwigsburg, Germany
8 Department of Hematology/Oncology, St Marien Hospital, Amberg, Germany
9 Private Practice Oncology/Hematology, Dresden, Germany
10 Department of Gastroenterology and Hemato-Oncology, University of Cologne, Cologne, Germany
11 Private Practice Oncology/Hematology, Memmingen, Germany
12 Private Practice Oncology/Hematology, Landshut, Germany
13 Department of Visceral Surgery, Kantonsspital Aarau, Aarau, Swiss
14 Clinic for Radiology, Charité-Universitätsmedizin Berlin, Berlin, Germany
15 Department of Diagnostic and Interventional Radiology, Ulm University Medical Center, Ulm, Germany
16 Biostatistics—Institute of Clinical Cancer Research (IKF) at Northwest Hospital, UCT-University Cancer Center, Frankfurt Am Main, Germany
17 Institute of Epidemiology and Medical Biometry, Ulm University, Ulm, Germany
18 Biostatistics, CCRC Cancer Clinical Research Consulting, Duesseldorf, Germany
19 Institute of Molecular Oncology and Stem Cell Biology, Ulm University Hospital, Ulm, Germany
Lukas Perkhofer, MD; e-mail: lukas.perkhofer@uniklinik-ulm.de.
10 9 2024
06 6 2024
06 6 2024
42 26 30943104
24 7 2023
3 1 2024
22 3 2024
© 2024 by American Society of Clinical Oncology
2024
American Society of Clinical Oncology
https://creativecommons.org/licenses/by-nc-nd/4.0/ Creative Commons Attribution Non-Commercial No Derivatives 4.0 License: http://creativecommons.org/licenses/by-nc-nd/4.0/

PURPOSE

First-line therapy options in advanced cholangiocarcinoma (CCA) are based on the ABC-02 trial regimen (gemcitabine/cisplatin [G/C]). The NIFE trial examined nanoliposomal irinotecan/fluorouracil/leucovorin (nal-IRI/FU/LV) as alternative first-line therapy in advanced CCA.

METHODS

NIFE is a prospective, open-label, randomized, multicenter phase II study that aimed at detecting efficacy comparable with the standard treatment. Patients with advanced CCA were randomly assigned (1:1) to receive nal-IRI/FU/LV (arm A) or G/C (arm B). Stratification parameters were intrahepatic versus extrahepatic CCA, sex, and Eastern Cooperative Oncology Group (ECOG; 0/1). Arm A was designed as a Simon's optimal two-stage design and arm B served as a randomized control group. The primary goal was to exclude an inferior progression-free survival (PFS) at 4 months of only 40%, while assuming a rate of 60% on G/C population.

RESULTS

Between 2018 and 2020, overall 91 patients were randomly assigned to receive nal-IRI/FU/LV (n = 49) or G/C (n = 42). The NIFE trial formally met its primary end point with a 4-month PFS rate of 51% in patients receiving nal-IRI/FU/LV. The median PFS was 6 months (2.4-9.6) in arm A and 6.9 months (2.5-7.9) in arm B. Median overall survival (OS) was 15.9 months (10.6-20.3) in arm A and 13.6 months (6.5-17.7) in arm B. The exploratory comparison of study arms suggested a numerical but statistically not significant advantage for nal-IRI/FU/LV (hazard ratio for PFS, 0.85 [95% CI, 0.53 to 1.38] and for OS, 0.94 [95% CI, 0.58 to 1.50]). Analysis for stratification parameters revealed no differences for sex and ECOG, but for tumor localization. The objective response rate was 24.5% with nal-IRI/FU/LV and 11.9% with G/C. No unexpected toxicities occurred. AEs related to nal-IRI/FU/LV were mainly GI and to G/C hematologic.

CONCLUSION

Treatment of advanced CCA with nal-IRI/FU/LV demonstrated efficacy in first-line therapy without new safety findings and merits further validation.

OPEN-ACCESSTRUE
==== Body
pmcINTRODUCTION

Cholangiocarcinoma (CCA) ranks 10th in Western World tumor statistics in terms of prevalence but is the fifth common cause of cancer-related deaths.1 The incidence, particularly of intrahepatic CCA (ICCA), is continuously rising.2,3 In advanced CCA, today's standard-of-care (SOC) first-line therapy for patients with a good performance status (PS; Eastern Cooperative Oncology Group [ECOG] 0-1) is gemcitabine/cisplatin (G/C)–based.4,5 This combination showed superior median progression-free survival (mPFS: G/C 8.0 v G 5.0 months; P < .001) and median overall survival (mOS: G/C 11.7 v G 8.1 months; hazard ratio [HR], 0.64 [95% CI, 0.52 to 0.80]; P < .001) compared with single-agent gemcitabine in the phase III ABC-02 trial independent of the tumor localization also including gallbladder and ampullary cancer. Considering the low survival times with G/C, various trials attempted to improve the outcome of first-line therapy of advanced CCA but largely failed.6-10 Recently, two phase-III trials demonstrated moderate improvement of OS in respective phase III trials with the addition of PD-L1 or PD-1 inhibition to G/C.11,12

CONTEXT

Key Objective

The NIFE trial aims to evaluate nanoliposomal irinotecan/fluorouracil/leucovorin (nal-IRI/FU/LV) as an alternative palliative first-line therapy in advanced cholangiocarcinoma (CCA).

Knowledge Generated

To our knowledge, this trial presents a first comprehensive analysis of nal-IRI/FU/LV as first-line therapy of advanced CCA and demonstrated clinical efficiency. The treatment was feasible and the toxicity profile manageable.

Relevance (E.M. O'Reilly)

This study evaluates a non-platinum regimen in the front-line treatment and demonstrates a signal of interest relative to standard of care cisplatin and gemcitabine in a small randomized phase II trial. Further development of nal-IRI/FU/LV in this disease setting appears justified.*

*Relevance section written by JCO Associate Editor Eileen M. O'Reilly, MD.

As shown for other solid cancers, nanoliposomal irinotecan (nal-IRI) added efficacy by an extended plasma half-life, increased intratumoral drug concentration compared with conventional irinotecan13,14 and proved effectiveness in the second-line therapy of advanced CCA.15 In this setting, nal-IRI/FU/leucovorin (fluorouracil/LV) was superior to only FU/LV after G/C in a phase IIb trial with a significantly prolonged mPFS (7.1 months v 1.4 months; HR, 0.56 [95% CI, 0.39 to 0.81]; P = .0019). Interestingly, the effect was most pronounced for gallbladder cancer.15 In the NIFE trial, we investigated nal-IRI/FU/LV as first-line therapy of advanced CCA in a randomized phase II trial.

METHODS

Study Design

The NIFE trial is a prospective, randomized, controlled, open-label, phase II multicenter study recruiting patients at 21 German centers.

Patients age 18 years and older with a good PS (ECOG 0-1) and histologically confirmed, nonresectable, locally advanced or metastatic adenocarcinoma of the ICCA or extrahepatic CCA (ECCA) were included in the study. Nonresectability had to be determined by a local multidisciplinary tumor board. Patients had to have at least one measurable lesion defined by RECIST 1.1 at the time of enrollment. Further inclusion criteria were an adequate hematologic, hepatic, and renal function, and exclusion of clinically significant cardiovascular disease or previous (<3 years)/concurrent malignancy other than CCA.

The study was approved by the ethics committee of Ulm University as the leading ethics committee for all German sites (reference number 11/17). In addition, local ethics committees approved the participating sites. The trial is registered at ClinicalTrials.gov (identifier: NCT03044587) and the European Clinical Trials Database (2016-002467-34). All patients signed informed consent according to the International Conference on Harmonisation of Good Clinical Practice guidelines and the principles of the Declaration of Helsinki.

Patients

Eligible patients (age 18 years and older) had a histologically confirmed, nonresectable, locally advanced or metastatic CCA. Disease had to be measurable or assessable according to RECIST 1.1. Further inclusion criteria were ECOG PS of 0 or 1, and adequate renal, hepatic, cardiac, and hematologic function as well as written informed consent. Exclusion criteria included the medical history of preexisting lung disease, past or current history of other malignancies except basal and squamous cell carcinoma of the skin, in-situ carcinoma of the cervix, T1a or T1b prostate carcinoma, or superficial bladder tumor (Ta, Tis, and T1), as well as other curatively treated malignant diseases without recurrence after at least 5 years of follow-up. No palliative chemotherapy for CCA was allowed before study entry; adjuvant therapy was allowed when finished ≥6 months before inclusion.

Procedures

Patients were randomly assigned 1:1 to receive either nal-IRI/FU/LV (arm A) or G/C (arm B) by study investigators using an interactive web response system (Trium Analysis Online GmbH, Munich, Germany) and a stratified block randomization schedule with a block size of 4. Stratification factors were primary site (intrahepatic v extrahepatic), WHO PS (ECOG 0 v ECOG 1), and sex (male v female). Treatment doses in arm A were as follows: nal-IRI 80 mg/m2, FU 2,400 mg/m2, LV 400 mg/m2, once every 2 weeks and in arm B: cisplatin 25 mg/m2, gemcitabine 1,000 mg/m2 once per day on days 1 and 8, once every 3 weeks. Treatment continued until disease progress, intolerable toxicity, or withdrawal of consent. Tumor assessment according to RECIST 1.1 with either contrast-enhanced multislice computed tomography (CT) or magnetic resonance imaging of the abdomen and enhanced multislice thoracic CT scan had to be performed within 28- days before therapy start and repeated every 8 weeks during treatment.

The European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire (QLQ) BIL21, QLQ–C30, and Hospital Anxiety and Depression Scale D questionnaires were repetitively recorded throughout the therapy. Follow-up documentation was performed every 8 weeks for the assessment of survival status, anticancer treatments, and safety.

Statistical Analysis and Random Assignment

The statistical considerations were based on the experimental arm A (nal-IRI/FU/LV), whereas arm B served as an internal randomized control to verify the baseline hypothesis. Stratified permutated block randomization was applied to ensure balanced prognostic groups by primary site (ICCA v ECCA), sex (male v female), and WHO PS (ECOG 0 v ECOG 1). The primary end point was determined as PFS rate at 4 months in arm A and was defined as the proportion of patients with nonprogressive disease 4 months after random assignment. A previous meta-analysis of published phase II and III trials over the past decades calculated mPFS times ranging from 4.1 to 5.5 months in the first-line therapy of advanced CCA.16,17 Therefore, Simon's optimal two-stage design was used for sample size calculation. The study tested the null hypothesis H0: <40% of patients are progression-free by 4 months and the alternative hypothesis: more than 60% of patients are progression-free by 4 months. An interim analysis, performed after the first 18 patients in arm A, allowed for early stopping because of futility. If seven or less patients were progression-free at 4 months, H1 could be rejected, and the study would have been terminated. If eight or more patients free of progression were observed, another 28 patients in each treatment group would have been included. At the final analysis, the null hypothesis would have been rejected by means of the respective confidence interval if 24 or more of the total 46 patients had progressed. With this design (alpha error of 10% [significance level], power of 90%) a sample size of 46 patients per arm (92 patients in total) was required. Patients without sufficient staging information at ≥4 months were counted as failures with respect to the primary end point.

The secondary end points included PFS, objective response rate (ORR) according to RECIST 1.1, OS, and safety parameters. PFS was defined as the number of months from the date of assignment to the date of death or progression, whichever occurred earlier (per RECIST 1.1). OS was defined as the number of months from the date of patient random assignment until the date of death from any cause. The efficacy analysis was performed using the intention-to-treat (ITT) population including all patients who were registered and randomly assigned to this study. The safety analysis included all randomly assigned patients who received at least one dose of study medication. Except for the primary end point, as described above, all analyses and calculations were performed on the basis of the data available for each item. Incomplete time-to-event observations were handled as censored measurements. All parameters were evaluated in a descriptive manner, and values are presented as mean (±standard deviation) and median (range) for continuous variables. Dichotomic variables are presented as absolute numbers (frequency) as well as percent. For survival data analysis, the Kaplan-Meier method with associated 95% CIs was used. All statistical analyses were conducted using SAS version 9.4 (SAS Institute, Inc, Cary, NC).

Role of the Funding Source

The NIFE trial was supported by an unrestricted grant from Servier. The supporting party had no influence on data collection, analysis or interpretation, trial design, patient recruitment, or any aspect pertinent to the study.

RESULTS

Between January 2018 and September 2020, 21 German sites enrolled a total of 93 patients in the trial. Forty-nine were randomly assigned to the experimental arm A and 42 to the SOC arm B. Two patients randomly assigned in arm B had to be excluded from the ITT population (n = 91) because of inappropriate random assignment (Fig 1). Both arms were well balanced for baseline patients and tumor characteristics (Table 1).

FIG 1. CONSORT diagram. G/C, gemcitabine/cisplatin; IC/EC, inclusion criteria/exclusion criteria; ITT, intention-to-treat; nal-IRI/FU/LV, nanoliposomal irinotecan/fluorouracil/leucovorin.

TABLE 1. Baseline Characteristics

Baseline Characteristic	ITT Population (N = 91)	
Arm A: Nal-Iri/FU/LV (n = 49)	Arm B: G/C (n = 42)	
Sex, No. (%)			
 Male	29 (59.2)	25 (59.5)	
 Female	20 (40.8)	17 (40.5)	
Age, years, median (range)	65.0 (33-82)	65.5 (46-83)	
ECOG performance status, No. (%)			
 0	28 (57.1)	27 (64.3)	
 1	21 (42.9)	15 (35.7)	
Tumor localization, No. (%)			
 ICCA	34 (69.4)	32 (76.2)	
 ECCA	15 (30.6)	10 (23.8)	
Disease classification, No. (%)			
 Locally advanceda	20 (40.8)	15 (35.7)	
 Metastatic	29 (59.2)	27 (64.3)	
WHO differentiation grade, No. (%)			
 Well differentiated (G1)	3 (6.1)	—	
 Fairly differentiated (G2)	22 (44.9)	16 (38.1)	
 Poorly differentiated (G3)	5 (10.2)	8 (19.0)	
 Undifferentiated (G4)	1 (2.0)	—	
 Not specified (Gx)	18 (36.7)	18 (42.9)	
Previous anticancer therapy, No. (%)			
 Tumor resection	11 (22.4)	12 (28.6)	
 Adjuvant chemotherapy	1 (2.0)	2 (4.8)	
 Adjuvant radiotherapy/chemoradiotherapy	2 (4.1)	—	
Abbreviations: CCA, cholangiocarcinoma; ECCA, extrahepatic CCA; ECOG, Eastern Cooperative Oncology Group; G/C, gemcitabine/cisplatin; ICCA, intrahepatic CCA; ITT, intention-to-treat; nal-IRI/FU/LV, nanoliposomal irinotecan/fluorouracil/leucovorin.

a Patient has only locally advanced sites of disease.

Tumor localization was mainly intrahepatic, with 72.5% (n = 66), and 27.5% of the tumors were extrahepatic (n = 25). Metastatic disease was present in 61.5% (n = 56) of patients, primarily affecting the liver (41.8%), lymph nodes (23.1%), and lung (15.4%). Twenty-three patients (25.3%) had previous major surgery with a median time to study inclusion of 2 months in arm A and 7.8 months in arm B. Of these patients, three received adjuvant chemotherapy and two adjuvant radiotherapy. Three patients in arm A had a R2 resection (Table 1).

Patients in arm A received a mean of 13.2 cycles (1-47) of treatment with a mean duration of treatment of 7.2 months (0.4-26.7). Patients in arm B received a mean of 14.3 cycles (1-52) with a mean duration of treatment of 5.9 months.

Tumor Response

The disease control rate after 2 months was 57.1% (n = 28/49) for arm A and 54.8% for arm B (n = 23/42; odds ratio [OR], 1.1; P = .8354). The ORR was 24.5% (n = 12/49) with nal-IRI/FU/LV and 11.9% (n = 5/42) with G/C (OR, 2.4; P = .1780). Best responses in arm A were two patients (4.1%) with a complete response (CR) and 10 (20.4%) with a partial response (PR) and in arm B five patients (11.9%) with a PR (Table 2; Fig 2). Response assessment by blinded imaging central review proved comparable results (Appendix Table A1, online only).

TABLE 2. Outcomes

Efficacy	ITT Population (n = 91)	
Arm A: Nal-Iri/FU/LV (n = 49)	Arm B: G/C (n = 42)	
Tumor response, No. (%)			
 Disease control rate	28 (57.1)	23 (54.8)	
 Overall response rate	12 (24.5)	5 (11.9)	
  Complete remission	2 (4.1)	0	
  Partial remission	10 (20.4)	5 (11.9)	
  Stable disease	16 (32.7)	20 (47.6)	
  Progressive disease	14 (28.6)	8 (19.0)	
  Not evaluablea	7 (14.3)	9 (21.4)	
PFS at 4 months,b No. (%)	25/49 (51.0)	25/42 (59.5)	
 ICCA	14/34 (41.2)	23/32 (71.9)	
 ECCA	11/15 (73.3)	2/10 (20.0)	
PFS, months, median	6.0	6.9	
 ICCA, No. (%)	34 (3.5)	32 (7.7)	
 ECCA, No. (%)	15 (9.6)	10 (1.8)	
OS, months, median	15.7	13.6	
 ICCA, No. (%)	34 (13.5)	32 (16.4)	
 ECCA, No. (%)	15 (18.2)	10 (6.3)	
Abbreviations: CCA, cholangiocarcinoma; ECCA, extrahepatic CCA; G/C, gemcitabine/cisplatin; ICCA, intrahepatic CCA; ITT, intention-to-treat; nal-IRI/FU/LV, nanoliposomal irinotecan/fluorouracil/leucovorin; OS, overall survival; PFS, progression-free survival.

a Patients not evaluable had only baseline imaging without follow-up imaging.

b Patients lost to follow-up before 4 months were considered as a failure to the end point.

FIG 2. Waterfall plot of best overall response. Each bar represents one patient and describes the best response assessment during the trial (relation of shortest tumor diameter to baseline assessment according to RECIST [version 1.1]). Arm A: nal-IRI/FU/LV blue bars, arm B: gemcitabine/cisplatin red bars. G/C, gemcitabine/cisplatin; nal-IRI/FU/LV, nanoliposomal irinotecan/fluorouracil/leucovorin.

Survival and Disease Progression

At the data cutoff, median follow-up time was 13.5 months (IQR, 5.6-21.8). The experimental arm A with nal-IRI/FU/LV formally met the predefined primary end point with a PFS rate of 51% (n = 25/49) at 4 months. In arm B, 59.5% (n = 25/42) of G/C-treated patients were progression-free at 4 months. mPFS was 6 months (95% CI, 2.37 to 9.59) with nal-IRI/FU/LV and 6.9 months (95% CI, 2.46 to 7.82) with G/C in the ITT population (Fig 3A; HR, 0.85 [95% CI, 0.53 to 1.38; P = .52). mOS was 15.7 months (95% CI, 10.15 to 20.20) in arm A and 13.6 months (95% CI, 6.51 to 17.68) in arm B (Fig 3B; Table 2; HR, 0.94 [95% CI, 0.58 to 1.50]; P = .78). For the OS analysis, the event numbers were 39 (79.6%) in arm A and 31 (73.8%) in arm B. A second-line therapy was initiated in 32 patients (65.3%) after nal-IRI-/FU/LV (arm A) and in 22 patients (52.4%) after first-line G/C (arm B; further line therapies; Appendix Tables A2 and A3).

FIG 3. PFS and OS in the ITT population. (A) PFS in patients randomly assigned to nal-IRI/FU/LV (arm A, n = 49) or gemcitabine/cisplatin (arm B, n = 42). (B) OS in patients randomly assigned to nal-IRI/FU/LV (arm A, n = 49) or gemcitabine/cisplatin (arm B, n = 42). G/C, gemcitabine/cisplatin; HR, hazard ratio; ITT, intention-to-treat; nal-IRI/FU/LV, nanoliposomal irinotecan/fluorouracil/leucovorin; OS, overall survival; PFS, progression-free survival.

Subgroup Analysis

According to predefined strata, subgroup analyses were performed. In the analysis according to extra- versus intra-hepatic tumor localization, mPFS in the ICCA group was 3.5 months (95% CI, 2.10 to 6.05) in patients treated with nal-IRI/FU/LV (n = 34) and 7.7 months (95% CI, 6.05 to 9.46) in G/C-treated patients (n = 32). In the ECCA group, the 15 patients treated with nal-IRI/FU/LV had a mPFS of 9.6 months (95% CI, 1.94 to 15.67) compared with 1.8 months (95% CI, 0.16 to 6.87) in the 10 G/C-treated patients (Fig 4A; Table 2; Appendix Fig A1A). mOS in ICCA was 13.5 months in arm A (95% CI, 7.59 to 20.01) versus 16.4 months in arm B (95% CI, 7.46 to 18.30). In ECCA, the exploratory analysis showed a mOS of 18.2 months (95% CI, 8.67 to 30.95) in arm A and 6.3 months (95% CI, 0.16 to not evaluable) in arm B (Fig 4B; Table 2; Appendix Fig A1B).

FIG 4. Efficacy analyses in subgroups for (A) PFS and (B) OS. Forest plots with indicated analyses: (A) HRs for progression or death with 95% CIs and (B) HRs for death with 95% CIs. CCA, cholangiocarcinoma; ECOG, Eastern Cooperative Oncology Group; G/C, gemcitabine/cisplatin; HR, hazard ratio; nal-IRI/FU/LV, nanoliposomal irinotecan/fluorouracil/leucovorin; OS, overall survival; PFS, progression-free survival.

The analysis of mPFS according to the PS of the patients showed some advantage for G/C-treated patients with ECOG 0 and for nal-IRI/FU/LV with ECOG 1 being both not translated into major differences in mOS (Figs 4A and 4B; Appendix Table A4). Interestingly, analysis for sex also suggested some differences in mPFS and mOS with a certain advantage for male patients treated with nal-IRI/FU/LV and for female patients treated with G/C (Figs 4A and 4B; Appendix Table A4). The differences in mPFS and mOS were not seen in the per protocol analysis (patients with at least one dose of chemotherapy and one subsequent tumor assessment) with adjusted results for sex and PS between both treatment groups (data not shown).

A post hoc analysis revealed some age-specific differences concerning therapy with the cutoff set at 65 years (Figs 4A and 4B).

Safety

The safety profiles of both treatment arms were consistent with previous findings.15,18 No unexpected adverse events were reported. In general, there were more GI disorders in the nal-IRI/FU/LV group, with Common Terminology Criteria for Adverse Events (CTC-AE) grade 3-4 diarrhea (22.4%), nausea (12.2%), and mucositis (2%). G/C was associated with more blood system disorders, in particular grade 3-4 neutropenia (21.9%) and anemia (26.8%; Table 3). No CTC-AE grade 5 toxicity occurred in the trial. The main reason for dose modifications in both arms was toxicity, with a frequency of 22.4% (each n = 11) for nal-IRI and FU, 35.7% (n = 15) for cisplatin, and 28.6% (n = 12) for gemcitabine. Treatment adjustment was necessary in the mean for three cycles (1-20) in arm A and 3.5 cycles (1-12) in arm B per patient.

TABLE 3. Adverse Events of Interest (ITT population) According to CTC-AE V 4.0

Event	Any Grade	Grade 3-4	
Arm A: Nal-IRI/FU/LV (n = 49)	Arm B: G/C (n = 42)	Arm A: Nal-IRI/FU/LV (n = 49)	Arm B: G/C (n = 42)	
Blood system disorders					
 Neutropenia	10.2	29.3	8.2	21.9	
 Febrile neutropenia	2.0	0	2.0	0	
 Leukopenia	14.3	24.4	0	12.2	
 Thrombocytopenia	14.3	24.4	2.0	9.8	
 Anemia	26.5	56.1	4.1	26.8	
GI disorders					
 Diarrhea	75.5	19.5	22.4	2.4	
 Nausea	59.2	43.9	12.2	0	
 Mucositis, oral	16.3	2.4	2.0	0	
 Vomiting	36.7	14.6	4.1	0	
General disorders					
 Fatigue	57.1	53.7	4.1	2.4	
Investigations					
 Weight decreased	24.5	4.9	0	0	
NOTE. Adverse event terms were derived from the case report forms. All events reported irrespective of whether they were reported as related to study treatment.

Abbreviations: CTC-AE, Common Terminology Criteria for Adverse Events; G/C, gemcitabine/cisplatin; ITT, intention-to-treat; nal-IRI/FU/LV, nanoliposomal irinotecan/fluorouracil/leucovorin.

DISCUSSION

So far, CCA remains a difficult-to-treat tumor with a poor prognosis. The mainstay of first-line treatment is the combination chemotherapy with G/C. Although G/C is efficacious, it is not well tolerated by all patients and an expansion of the therapeutic armamentarium would be desirable.17 The addition of the checkpoint inhibitors durvalumab or pembrolizumab to G/C is a first successful step ahead by improving OS in first-line treatment of advanced CCA.11,12 In this study, we investigated the combination of nal-IRI/FU/LV with a randomized SOC control group in patients with treatment-naïve, unresectable CCA. The aim of the trial was to find an alternative regimen in first-line therapy that is comparable with G/C as this is not feasible to all patients. To control for selection bias, we included a randomized control arm with the standard treatment G/C.

Baseline characteristics of the treatment groups were well balanced for age and sex, with some slight deviations regarding ECOG PS, and metastasis. Reasons for imbalance are assumed to be due to small subgroup numbers.

The primary end point of the trial was formally met with a 4-month PFS rate of more than 50% in the experimental arm. In our trial, the mPFS times were numerically in favor of the SOC arm, and in terms of mOS, this was vice versa. As these were secondary end points and the trial was not powered for direct comparison of the trial arms, any interpretation has to be done with caution. On the basis of our data and compared with published evidence, we suggest a reasonable efficacy in both arms, without showing clear numerical superiority of either arm A or B. The time-to-event efficacy estimations for G/C presented here are comparable or even slightly better in our study than those published in the phase III trials ABC-02 (mPFS, 8 months; mOS, 11.7 months),18 TOPAZ-1 (mPFS, 5.7 months; mOS, 11.5 months),11 and KEYNOTE-966 (mPFS, 5.6 months; mOS, 10.9 months).12

Disease control rate (DCR) was similar between both treatment arms (arm A: 57.1%; arm B 54.8%), and the ORR was higher in arm A with 24.5% (including two patients with CR) than in arm B with 11.9%. Compared with published data, DCR (for G/C in ABC-02: 81.4% and in TOPAZ-1: 82.6%) and ORR (for G/C: ABC-02 subgroup bile duct and ampullary 19% and TOPAZ-1 18.7%) were lower in arm B of this trial.11,18 This may be due to the extended collectives used in these trials with inclusion of gallbladder cancers ± ampullary cancers.

Subgroup analysis of the ABC-02 and KEYNOTE-966 trials revealed a marked benefit for intrahepatic and a lesser benefit for ECCA for G/C.12,18 ICCA and ECCA differ in their cells of origin, histopathologic characteristics, and mutational spectra. On the basis of sequencing studies, up to 50% of CCAs harbor targetable genetic alterations; however, these are almost exclusively found in ICCAs. Targeted therapies already start to revolutionize treatment in advanced ICCA when FGFR2 fusions/rearrangements or IDH1 mutations are present.19-21 By contrast, HER2 overexpression/amplification is the only relevant druggable molecular alteration found so far at a reasonable frequency in ECCA.22 Taken together, ICCA and ECCA exhibit substantial biologic differences, challenging a one-size-fits-all therapeutic concept. In the NIFE trial, stratification by ICCA and ECCA revealed substantial differences in mPFS and mOS. Nal-IRI/FU/LV showed a mPFS in patients with ICCA of 3.5 months (mOS, 13.5 months) and 9.6 months (mOS, 18.2 months) in patients with ECCA. The corresponding data for G/C were mPFS 7.7 months (mOS, 16.4 months) in ICCA and 1.8 months (mOS, 6.3 months) in patients with ECCA. To render pure coincidence unlikely in the analysis for ECCA, a Cox proportional hazard model was employed to test for heterogeneity (P = .0026). For the subgroup analyses, the small numbers of patients is a critical point that has to be considered. Keeping this in mind, the data presented suggest that nal-IRI/FU/LV might have a particular benefit as first-line treatment in patients with ECCA and G/C in patients with ICCA. This suggestion is supported by another phase II trial using FU and irinotecan in the triple combination FOLFIRINOX as first -line therapy in advanced CCAs. This trial revealed inferiority for ICCAs but superiority for ECCAs compared with G/C6 indicating that chemotherapeutic regimens might have different efficacy in ICCA and ECCA, respectively. Of note, this effect was not obvious in the 2nd-line setting for ECCA and only for gallbladder cancer in the NIFTY phase II trial.15 Since so far there are only a few targeted strategies for ECCA apart from targeting human epidermal growth factor receptor 222 or BRAF,23 it appears worthwhile to further examine nal-IRI/FU/LV, particularly in this subgroup of patients with treatment-naïve CCA. The rate of subsequent chemotherapies was higher in arm A (65.3%) than in arm B (52.4%), and comparable with the TOPAZ-1 trial for G/C (49.4%).11 Interestingly, the majority of patients treated in arm B received an irinotecan-containing regimen for second-line therapy.

There were no unexpected safety signals in both treatment arms. In our cohort, GI disorders including diarrhea and nausea were more common, to a greater extend as described in the NIFTY trial including an Asian population15 but closer to the NAPOLI-1 phase III trial with second-line therapy of patients with advanced pancreatic cancer.24 Patients included in the trial were not tested for UGT1A enzyme activity.

In summary, to our knowledge, NIFE is the first prospective trial demonstrating efficacy of nal-IRI/FU/LV in the first-line therapy setting of advanced CCA and this regimen merits further validation in a larger phase III trial.

ACKNOWLEDGMENT

The authors thank all the patients who participated in the trial and the study investigators, nurses, and other members of the multidisciplinary teams. The authors thank the AIO Studien gGmbH (Berlin, Germany) for sponsoring the trial and Servier for funding. The authors thank the IKF (Frankfurt/Main, Germany), which randomly assigned participants, managed and monitored the data, and did the primary data analysis. The authors also thank members of the independent data monitoring committee for their oversight of the trial.

PRIOR PRESENTATION

SUPPORT

CLINICAL TRIAL INFORMATION

DATA SHARING STATEMENT

AIO Studien gGmbH acting as the legal sponsor is committed to provide additional data to researchers with the goal of furthering science. Data that will be considered for disclosure includes individual participant data that underlie the results reported in this article (text, tables, figures, and appendices). In addition, the study protocol—including consent forms, statistical analysis plan and analytic code—can be made available. All data shared must be anonymized to protect the privacy of the patients who participated in the trial, in accordance with applicable laws and regulations and in compliance with the International Conference on Harmonization and Good Clinical Practice. Researchers should provide a methodologically sound proposal directed to the corresponding author for approval to gain access to the required data. Shared data are only to be used to achieve aims in the approved proposal.

AUTHOR CONTRIBUTIONS

Conception and design: Thomas J. Ettrich, Ludwig Fischer von Weikersthal, Andreas W. Berger, Rainer Muche, Thomas Seufferlein, Lukas Perkhofer

Provision of study materials or patients: Dominik P. Modest, Marianne Sinn, Jana K. Striefler, Thorsten Goetze, Eike Gallmeier, Ludwig Fischer von Weikersthal, Lutz Jacobasch, Michael Niedermeier, Michael Sohm, Daniel Vogele, Thomas Seufferlein

Collection and assembly of data: Thomas J. Ettrich, Dominik P. Modest, Marianne Sinn, Jana K. Striefler, Bernhard Opitz, Thorsten Goetze, Eike Gallmeier, Stefan Angermeier, Ludwig Fischer von Weikersthal, Lutz Jacobasch, Dirk Waldschmidt, Michael Sohm, Andreas W. Berger, Uli Fehrenbach, Clarissa Hosse, Thomas Seufferlein, Lukas Perkhofer

Data analysis and interpretation: All authors

Manuscript writing: All authors

Final approval of manuscript: All authors

Accountable for all aspects of the work: All authors

AUTHORS' DISCLOSURES OF POTENTIAL CONFLICTS OF INTEREST

Nanoliposomal Irinotecan With Fluorouracil and Leucovorin or Gemcitabine Plus Cisplatin in Advanced Cholangiocarcinoma: A Phase II Study of the AIO Hepatobiliary-YMO Cancer Groups (NIFE-AIO-YMO HEP-0315)

The following represents disclosure information provided by authors of this manuscript. All relationships are considered compensated unless otherwise noted. Relationships are self-held unless noted. I = Immediate Family Member, Inst = My Institution. Relationships may not relate to the subject matter of this manuscript. For more information about ASCO's conflict of interest policy, please refer to www.asco.org/rwc or ascopubs.org/jco/authors/author-center.

Open Payments is a public database containing information reported by companies about payments made to US-licensed physicians (Open Payments).

APPENDIX

FIG A1. (A) PFS in the ITT population for ICCA and ECCA subgroups. (B) OS in the ITT population for ICCA and ECCA subgroups. Thick marks indicate censored observations. CCA, cholangiocarcinoma; ECCA, extrahepatic CCA; G/C, gemcitabine/cisplatin; HR, hazard ratio; ICCA, intrahepatic CCA; ITT, intention-to-treat; mPFS, median PFS; nal-IRI/FU/LV, nanoliposomal irinotecan/fluorouracil/leucovorin; OS, overall survival; PFS, progression-free survival.

TABLE A1. Response Assessment by Blinded Imaging Central Review (ITT)

Efficacy Analysis	Blinded Imaging Central Review (N = 67), No. (%)	
Arm A: Nal-IRI/FU/LV (n = 36)	Arm B: G/C (n = 31)	
Tumor response			
 Disease control rate	23 (63.9)	17 (54.8)	
 Overall response rate	9 (25)	3 (9.7)	
  Complete remission	1 (2.8)	1 (3.2)	
  Partial remission	8 (22.2)	2 (6.5)	
  Stable disease	14 (38.9)	14 (45.2)	
  Progressive disease	6 (16.6)	5 (16.1)	
  Not evaluablea	7 (19.4)	9 (29)	
PFS at 4 monthsb	19/36 (52.8)	17/31 (54.8)	
Abbreviations: G/C, gemcitabine/cisplatin; ITT, intention-to-treat; nal-IRI/FU/LV, nanoliposomal irinotecan/fluorouracil/leucovorin; PFS, progression-free survival.

a Patients not evaluable had only baseline imaging without follow-up imaging.

b Patients lost to follow-up before 4 months were considered as a failure to the end point.

TABLE A2. Further-Line Therapies: Arm A (nal-IRI/FU/LV)

Therapy	Therapy Line	
Second	Third	>Third	
Gemcitabine/cisplatin	20	3		
FOLFOX	4	2	1	
Gemcitabine/oxaliplatin	4	4	—	
FOLFIRI	2	1	3	
Gemcitabine	1	—	—	
Melphalan	1	—	—	
Ivosidenib	—	—	2	
Pembrolizumab	—	2		
Paclitaxel	—	2	2	
Gemcitabine/nab-paclitaxel	—	—	1	
Regorafenib	—	1	—	
Total	32	15	8	
Abbreviations: FOLFIRI, folinic acid/FU/irinotecan; FOLFOX, folinic acid/FU/oxaliplatin; nal-IRI/FU/LV, nanoliposomal irinotecan/fluorouracil/leucovorin.

TABLE A3. Further-Line Therapies: Arm B (gemcitabine/cisplatin)

Therapy	Therapy Line	
Second	Third	>Third	
FOLFIRI	13	2	—	
FOLFOX	2	3	—	
Gemcitabine/oxaliplatin	1	—	—	
Gemcitabine	1	1	1	
Capecitabine	2	—	—	
Nal-IRI/FU/LV	1	—	1	
Selpercatinib	1	—	—	
Pemigatinib	—	—	2	
Gemcitabine/nab-paclitaxel	—	1	—	
Pertuzumab/trastuzumab	1	—	—	
Gemcitabine/capecitabine	—	—	1	
FU/Nab-paclitaxel	—	—	1	
Gemcitabine/cisplatin	—	1	—	
Oxaliplatin	—	1	—	
FU/cisplatin	—	—	1	
Total	22	9	7	
Abbreviations: FOLFIRI, folinic acid/FU/irinotecan; FOLFOX, folinic acid/FU/oxaliplatin; nal-IRI/FU/LV, nanoliposomal irinotecan/fluorouracil/leucovorin.

TABLE A4. Outcomes

Efficacy	ITT Population (N = 91)	
Arm A: Nal-IRI/FU/LV (n = 49), No. (%)	Arm B: G/C (n = 42), No. (%)	
Median PFS, months			
 ECOG 0	5.7 (28)	7.6 (27)	
 ECOG 1	8.9 (21)	3.8 (15)	
 Male	6.1 (29)	6.5 (25)	
 Female	6.0 (20)	7.6 (17)	
Median OS, months			
 ECOG 0	16.2 (28)	17.0 (27)	
 ECOG 1	14.2 (21)	6.3 (15)	
 Male	16.0 (29)	12.6 (25)	
 Female	14.2 (20)	17.7 (17)	
Abbreviations: ECOG, Eastern Cooperative Oncology Group; G/C, gemcitabine/cisplatin; ITT, intention-to-treat; nal-IRI/FU/LV, nanoliposomal irinotecan/fluorouracil/leucovorin; OS, overall survival; PFS, progression-free survival.

Presented in part at the 2021 European Society for Medical Oncology annual meeting, Paris, France, September 17th, 2021.

Supported by an unrestricted grant from Servier.

NCT03044587 (NIFE)

Thomas J. Ettrich

Consulting or Advisory Role: MSD, Roche, Sanofi, Bristol Myers Squibb, AstraZeneca, Merck Serono, Pierre Fabre, Servier, Lilly, Ipsen, Daiichi Sankyo Europe GmbH, AbbVie, Takeda

Research Funding: Baxalta/Shire, Lilly (Inst)

Travel, Accommodations, Expenses: Ipsen, Lilly

Dominik P. Modest

Honoraria: Merck Serono, Amgen, Servier, Bristol Myers Squibb, Taiho Pharmaceutical, Onkowissen, Merck, Pierre Fabre, AstraZeneca, Sanofi, Lilly, Takeda, GlaxoSmithKline, Seagen, Cor2Ed, Boehringer Ingelheim

Consulting or Advisory Role: Merck Serono, Amgen, Servier, Pierre Fabre, Lilly, Cor2Ed, Onkowissen, Regeneron, GlaxoSmithKline, Takeda

Research Funding: Amgen (Inst), Servier (Inst)

Travel, Accommodations, Expenses: Amgen, Merck Serono, Servier

Marianne Sinn

Honoraria: Roche Pharma AG, Falk Pharma

Research Funding: BioNTech SE (Inst), BeiGene (Inst), BMS GmbH & Co KG (Inst), Novartis/Pfizer (Inst), AstraZeneca (Inst), Institut Allergosan (Inst), Roche Pharma AG (Inst), Amgen (Inst)

Bernhard Opitz

Honoraria: Roche Pharma AG

Thorsten Goetze

Consulting or Advisory Role: Lilly, MSD Oncology, Bayer, Servier, Roche, Novartis, Incyte, Foundation Medicine, Bristol Myers Squibb

Speakers' Bureau: Lilly, MSD Oncology

Research Funding: Deutsche Forschungsgemeinschaft, Gemeinsamer Bundesausschuss, Deutsche Krebshilfe (Inst), Lilly (Inst), AstraZeneca (Inst), Incyte (Inst)

Lutz Jacobasch

Consulting or Advisory Role: BeiGene, AbbVie, Incyte

Travel, Accommodations, Expenses: Boehringer Ingelheim, Ipsen, Sanofi

Dirk Waldschmidt

Speakers' Bureau: AstraZeneca, Incyte, Roche Pharma AG, Servier, MSD Oncology, Ipsen, Boehringer Ingelheim

Travel, Accommodations, Expenses: AstraZeneca, Lilly, Servier, Ipsen

Uli Fehrenbach

Honoraria: Bayer Health, Siemens, Ipsen, Asahi Intecc

Travel, Accommodations, Expenses: Bayer Health

Timo Alexander Auer

Honoraria: Bayer Schering Pharma, Boston Scientific, BD Bard

Consulting or Advisory Role: Bayer Schering Pharma

Research Funding: Bayer Schering Pharma (Inst)

Disorn Sookthai

Stock and Other Ownership Interests: Bayer

Thomas Seufferlein

Honoraria: Falk Foundation, Servier, Pierre Fabre, BMS GmbH & Co KG, AstraZeneca, MSD Oncology, Takeda

Consulting or Advisory Role: Servier, Pierre Fabre, Cantargia AB, Boehringer Ingelheim, Mirati Therapeutics, Scandion Oncology, Olympus Medical Systems, BioNTech SE

Research Funding: Lilly/ImClone (Inst)

Travel, Accommodations, Expenses: Takeda

Lukas Perkhofer

Consulting or Advisory Role: AstraZeneca, Servier

Expert Testimony: AstraZeneca

Travel, Accommodations, Expenses: AstraZeneca

No other potential conflicts of interest were reported.

Thomas J. Ettrich

Consulting or Advisory Role: MSD, Roche, Sanofi, Bristol Myers Squibb, AstraZeneca, Merck Serono, Pierre Fabre, Servier, Lilly, Ipsen, Daiichi Sankyo Europe GmbH, AbbVie, Takeda

Research Funding: Baxalta/Shire, Lilly (Inst)

Travel, Accommodations, Expenses: Ipsen, Lilly

Dominik P. Modest

Honoraria: Merck Serono, Amgen, Servier, Bristol Myers Squibb, Taiho Pharmaceutical, Onkowissen, Merck, Pierre Fabre, AstraZeneca, Sanofi, Lilly, Takeda, GlaxoSmithKline, Seagen, Cor2Ed, Boehringer Ingelheim

Consulting or Advisory Role: Merck Serono, Amgen, Servier, Pierre Fabre, Lilly, Cor2Ed, Onkowissen, Regeneron, GlaxoSmithKline, Takeda

Research Funding: Amgen (Inst), Servier (Inst)

Travel, Accommodations, Expenses: Amgen, Merck Serono, Servier

Marianne Sinn

Honoraria: Roche Pharma AG, Falk Pharma

Research Funding: BioNTech SE (Inst), BeiGene (Inst), BMS GmbH & Co KG (Inst), Novartis/Pfizer (Inst), AstraZeneca (Inst), Institut Allergosan (Inst), Roche Pharma AG (Inst), Amgen (Inst)

Bernhard Opitz

Honoraria: Roche Pharma AG

Thorsten Goetze

Consulting or Advisory Role: Lilly, MSD Oncology, Bayer, Servier, Roche, Novartis, Incyte, Foundation Medicine, Bristol Myers Squibb

Speakers' Bureau: Lilly, MSD Oncology

Research Funding: Deutsche Forschungsgemeinschaft, Gemeinsamer Bundesausschuss, Deutsche Krebshilfe (Inst), Lilly (Inst), AstraZeneca (Inst), Incyte (Inst)

Lutz Jacobasch

Consulting or Advisory Role: BeiGene, AbbVie, Incyte

Travel, Accommodations, Expenses: Boehringer Ingelheim, Ipsen, Sanofi

Dirk Waldschmidt

Speakers' Bureau: AstraZeneca, Incyte, Roche Pharma AG, Servier, MSD Oncology, Ipsen, Boehringer Ingelheim

Travel, Accommodations, Expenses: AstraZeneca, Lilly, Servier, Ipsen

Uli Fehrenbach

Honoraria: Bayer Health, Siemens, Ipsen, Asahi Intecc

Travel, Accommodations, Expenses: Bayer Health

Timo Alexander Auer

Honoraria: Bayer Schering Pharma, Boston Scientific, BD Bard

Consulting or Advisory Role: Bayer Schering Pharma

Research Funding: Bayer Schering Pharma (Inst)

Disorn Sookthai

Stock and Other Ownership Interests: Bayer

Thomas Seufferlein

Honoraria: Falk Foundation, Servier, Pierre Fabre, BMS GmbH & Co KG, AstraZeneca, MSD Oncology, Takeda

Consulting or Advisory Role: Servier, Pierre Fabre, Cantargia AB, Boehringer Ingelheim, Mirati Therapeutics, Scandion Oncology, Olympus Medical Systems, BioNTech SE

Research Funding: Lilly/ImClone (Inst)

Travel, Accommodations, Expenses: Takeda

Lukas Perkhofer

Consulting or Advisory Role: AstraZeneca, Servier

Expert Testimony: AstraZeneca

Travel, Accommodations, Expenses: AstraZeneca

No other potential conflicts of interest were reported.
==== Refs
REFERENCES

1. Siegel RL , Miller KD , Jemal A : Cancer statistics, 2017. CA Cancer J Clin 67 :7-30, 2017 28055103
2. von Hahn T , Ciesek S , Wegener G , et al : Epidemiological trends in incidence and mortality of hepatobiliary cancers in Germany. Scand J Gastroenterol 46 :1092-1098, 2011 21692710
3. Saha SK , Zhu AX , Fuchs CS , et al : Forty-year trends in cholangiocarcinoma incidence in the U.S: Intrahepatic disease on the rise. Oncologist 21 :594-599, 2016 27000463
4. Voesch S , Bitzer M , Blodt S , et al : S3-Leitlinie: Diagnostik und Therapie des hepatozellulären Karzinoms und biliärer Karzinome–Version 2.0–Juni 2021, AWMF-Registernummer: 032-053OL. Z Gastroenterol 60 :e131-e185, 2022 35042250
5. Valle JW , Borbath I , Khan SA , et al : Biliary cancer: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up. Ann Oncol 27 :v28-v37, 2016 (suppl 5)27664259
6. Phelip JM , Desrame J , Edeline J , et al : Modified FOLFIRINOX versus CISGEM chemotherapy for patients with advanced biliary tract cancer (PRODIGE 38 AMEBICA): A randomized phase II study. J Clin Oncol 40 :262-271, 2022 34662180
7. Feng L , Wang Y , Xu H , et al : Comparison of different first-line systemic therapies in advanced biliary tract cancer based on updated random controlled trials: A systematic review and network meta-analysis. Biomed Res Int 2022 :1720696, 2022 36119936
8. Valle JW , Wasan H , Lopes A , et al : Cediranib or placebo in combination with cisplatin and gemcitabine chemotherapy for patients with advanced biliary tract cancer (ABC-03): A randomised phase 2 trial. Lancet Oncol 16 :967-978, 2015 26179201
9. Valle JW , Vogel A , Denlinger CS , et al : Addition of ramucirumab or merestinib to standard first-line chemotherapy for locally advanced or metastatic biliary tract cancer: A randomised, double-blind, multicentre, phase 2 study. Lancet Oncol 22 :1468-1482, 2021 34592180
10. Sharma A , Kalyan Mohanti B , Pal Chaudhary S , et al : Modified gemcitabine and oxaliplatin or gemcitabine + cisplatin in unresectable gallbladder cancer: Results of a phase III randomised controlled trial. Eur J Cancer 123 :162-170, 2019 31707181
11. Oh D-Y , He AR , Qin S , et al : Durvalumab plus gemcitabine and cisplatin in advanced biliary tract cancer. NEJM Evid 1 :EVIDoa2200015, 2022 38319896
12. Kelley RK , Ueno M , Yoo C , et al : Pembrolizumab in combination with gemcitabine and cisplatin compared with gemcitabine and cisplatin alone for patients with advanced biliary tract cancer (KEYNOTE-966): A randomised, double-blind, placebo-controlled, phase 3 trial. Lancet 401 :1853-1865, 2023 37075781
13. Adiwijaya BS , Kim J , Lang I , et al : Population pharmacokinetics of liposomal irinotecan in patients with cancer. Clin Pharmacol Ther 102 :997-1005, 2017 28445610
14. Roy AC , Park SR , Cunningham D , et al : A randomized phase II study of PEP02 (MM-398), irinotecan or docetaxel as a second-line therapy in patients with locally advanced or metastatic gastric or gastro-oesophageal junction adenocarcinoma. Ann Oncol 24 :1567-1573, 2013 23406728
15. Yoo C , Kim KP , Jeong JH , et al : 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. Lancet Oncol 22 :1560-1572, 2021 34656226
16. Eckel F , Schmid RM : Chemotherapy in advanced biliary tract carcinoma: A pooled analysis of clinical trials. Br J Cancer 96 :896-902, 2007 17325704
17. Jiang Y , Zeng Z , Zeng J , et al : Efficacy and safety of first-line chemotherapies for patients with advanced biliary tract carcinoma: A systematic review and network meta-analysis. Front Oncol 11 :736113, 2021 34650920
18. Valle J , Wasan H , Palmer DH , et al : Cisplatin plus gemcitabine versus gemcitabine for biliary tract cancer. N Engl J Med 362 :1273-1281, 2010 20375404
19. Abou-Alfa GK , Sahai V , Hollebecque A , et al : Pemigatinib for previously treated, locally advanced or metastatic cholangiocarcinoma: A multicentre, open-label, phase 2 study. Lancet Oncol 21 :671-684, 2020 32203698
20. Abou-Alfa GK , Macarulla T , Javle MM , et al : Ivosidenib in IDH1-mutant, chemotherapy-refractory cholangiocarcinoma (ClarIDHy): A multicentre, randomised, double-blind, placebo-controlled, phase 3 study. Lancet Oncol 21 :796-807, 2020 32416072
21. Zhu AX , Macarulla T , Javle MM , et al : Final overall survival efficacy results of ivosidenib for patients with advanced cholangiocarcinoma with IDH1 mutation: The phase 3 randomized clinical ClarIDHy trial. JAMA Oncol 7 :1669-1677, 2021 34554208
22. Javle M , Borad MJ , Azad NS , et al : Pertuzumab and trastuzumab for HER2-positive, metastatic biliary tract cancer (MyPathway): A multicentre, open-label, phase 2a, multiple basket study. Lancet Oncol 22 :1290-1300, 2021 34339623
23. Subbiah V , Lassen U , Elez E , et al : Dabrafenib plus trametinib in patients with BRAF(V600E)-mutated biliary tract cancer (ROAR): A phase 2, open-label, single-arm, multicentre basket trial. Lancet Oncol 21 :1234-1243, 2020 32818466
24. Wang-Gillam A , Li CP , Bodoky G , et al : Nanoliposomal irinotecan with fluorouracil and folinic acid in metastatic pancreatic cancer after previous gemcitabine-based therapy (NAPOLI-1): A global, randomised, open-label, phase 3 trial. Lancet 387 :545-557, 2016 26615328
