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The combination of 5-fluorouracil/leucovorin (5-FU/LV) plus oxaliplatin (FOLFOX) is widely acknowledged as the standard regimen for second-line treatment in patients with advanced biliary tract cancer. Nanoliposomal irinotecan (nal-IRI) has demonstrated its activity in patients with advanced pancreatic cancer. Recent studies have investigated the activity of nal-IRI in combination with 5-FU/LV for biliary tract cancer. However, the results have been contradictory. We conducted a meta-analysis to assess survival outcomes and response rates in randomised trials investigating the activity of nal-IRI in previously treated biliary tract cancer patients. We systematically collected potentially relevant findings from PubMed/Medline, the Cochrane library and EMBASE. Abstracts presented at major international oncological meetings were also reviewed. We extracted hazard ratios and 95% confidence intervals for progression-free survival and overall survival, as well as odds ratios and 95% confidence intervals for objective response rate. The outcomes of the accessible randomised studies evaluating the activity of nal-IRI plus 5-FU/LV were analysed. The combination therapy exhibited a statistically significant decrease in the risk of progression (hazard ratio 0.70; 95% confidence interval 0.50–0.97) when compared with 5-FU/LV alone. Additionally, the dual regimen yielded longer overall survival and a higher objective response rate. Our meta-analysis showed that nal-IRI plus 5-FU/LV had a superior activity in comparison with 5-FU/LV. Further investigations are required to elucidate the role of nal-IRI in this setting and to identify subgroups of patients who could derive the greatest benefit from its administration. • No evidence that doublet therapy is more effective than monotherapy in second-line treatment of biliary tract cancer. • FOLFOX demonstrated higher activity compared with active symptom control. • Two studies showed conflicting results assessing the activity of 5-FU/LV ± nal-IRI. • Our meta-analysis supports the role of nal-IRI in biliary tract cancer. [ABSTRACT FROM AUTHOR]

The preferred regimen for unresectable pancreatic cancer following gemcitabine-based chemotherapy is not well-established. This study compared the efficacy of (ⅰ) liposomal irinotecan (nal-IRI) plus 5-fluorouracil (5-FU)/leucovorin (LV) (nal-IRI/5-FU/LV) versus modified FOLFIRINOX (mFFX) and (ⅱ) nal-IRI/5-FU/LV versus FOLFIRI, respectively, and the safety of the three regimens each other, as second-line chemotherapies for unresectable pancreatic cancer. This was a retrospective single-center analysis of all patients who were administered nal-IRI/5-FU/LV, mFFX, or FOLFIRI from December 2014 to July 2021 as second-line chemotherapy for pancreatic cancer. The primary endpoint was the overall survival (OS) of all patients, excluding those with locally advanced pancreatic cancer. Regarding safety, we assessed the incidence of grade ≥3 adverse events of interest in all patients. A total of 137 patients (nal-IRI/5-FU/LV, n = 55; mFFX, n = 39; FOLFIRI, n = 43) were included. The median OS in the nal-IRI/5-FU/LV group, the mFFX group, and the FOLFIRI group was 7.4, 11.8, and 8.4 months, respectively. Compared with the nal-IRI/5-FU/LV group, the mFFX and FOLFIRI groups displayed a hazard ratio of 0.66 [95% confidence interval 0.40–1.08] and 0.87 [95% confidence interval 0.55–1.39], respectively. In the FOLFIRI group, the incidence of grade ≥3 treatment-related adverse events tended to be low among all three groups. Given the trend toward longer OS in the mFFX group and the lower incidence of adverse events in the FOLFIRI group, both mFFX and FOLFIRI, as well as nal-IRI/5-FU/LV, can be treatment options for second-line chemotherapy for unresectable pancreatic cancer. [ABSTRACT FROM AUTHOR]

Nanoliposomal irinotecan (nal-IRI) is a novel regimen for pancreatic cancer, featuring a longer half-life and an increased area under the concentration-time curve. This study aims to assess the safety and efficacy of nal-IRI as a second-line treatment for advanced pancreatic cancer. A systemic literature search was conducted based on articles published before September 26th, 2023 in databases, including PubMed, Cochrane Library, EMBASE and Web of Science. The fixed effects model was used to calculate the pooled mean difference for overall survival (OS) and progression-free survival (PFS), as well as the pooled odds ratio for the overall response rate (ORR) and the risk of adverse events. A total of 21 studies, including 3044 patients with locally advanced unresectable or metastatic pancreatic cancers, were considered eligible. The use of nal-IRI, combined with 5-fluorouracil and leucovorin, resulted in significantly improved PFS (pooled mean difference=1.01 months, 95 % confidence interval [CI]=0.97–1.05, p< 0.01) and OS (pooled mean difference=0.29 months, 95 %CI=0.18–0.39, p <0.01), as well as significantly better ORR (pooled odds ratio=2.06, 95 %CI=1.30–3.27, p =0.002) compared to other second-line regimens. Nonetheless, an increased risk of grade 3 or greater neutropenia, anemia, hypokalemia, diarrhea, and vomiting was also noted. Second-line treatments based on nal-IRI exhibited significantly improved PFS, OS, and ORR compared to other available treatments in advanced pancreatic cancer. Further research is necessary to corroborate these findings and define the role of nal-IRI in both first and later lines of therapy. [Display omitted] • Liposomal irinotecan resulted in significantly longer progression-free survival (pooled mean difference=1.01 months, 95 % CI=0.97–1.05). • Liposomal irinotecan showed significantly better overall survival (pooled mean difference=0.29 months (95 % CI=0.18–0.39). • The use of liposomal irinotecan led to better overall response rate (pooled odds ratio=2.06, 95 % CI=1.30–3.27). • Increased risks of neutropenia, anemia, hypokalemia, diarrhea, and vomiting were noted in patients on liposomal irinotecan. [ABSTRACT FROM AUTHOR]

This multicenter phase I/IIa study aimed to determine the recommended phase II dose (RP2D) and evaluate the safety and preliminary efficacy of liposomal irinotecan (nal-IRI), oxaliplatin, and S-1 (NASOX) as first-line treatment for advanced pancreatic adenocarcinoma. Patients with locally advanced or metastatic pancreatic adenocarcinoma without prior systemic treatment for advanced disease, aged ≥ 19 years, with measurable disease, and Eastern Cooperative Oncology Group performance status of 0–1 were eligible. The primary endpoints were to determine the dose-limiting toxicity (DLT) in the phase I cohort and overall response rate (ORR) in the phase IIa cohort. The intention-to-treat (ITT) analysis included patients who received the RP2D. In phase I, seven patients were screened, and six were assessed for DLT. None experienced DLT during the first cycle. The RP2D was determined as nal-IRI 50 mg/m2 and oxaliplatin 60 mg/m2 on day 1, S-1 40 mg/m2 twice daily on days 1–7 every 14 days. For the ITT (N = 41; 7, and 34 from phases I and IIa, respectively), the most common grade 3–4 treatment-emergent adverse events were neutropenia (31.7 %), enterocolitis (9.8 %), anorexia (7.3 %), and diarrhea (2.4 %). The ORR was 58.5 % (1 complete, and 23 partial responses). Two underwent conversion surgery; both achieved R0 resection. With median follow-up of 17.5 months, median progression-free survival was 6.5 months (95 % confidence interval [CI], 5.0–8.1) and median overall survival was 11.4 months (95 % CI, 9.8–15.5). NASOX exhibited a manageable safety profile and encouraging efficacy outcomes consistent with NALIRIFOX, showing potential to replace infusional 5-fluorouracil with oral S-1 in the triplet regimen. • In this Ph I/IIa trial, patients with advanced PDAC received 1 L NASOX every 2 weeks. • RP2D: nal-IRI 50 mg/m2, oxaliplatin 60 mg/m2 on D1, S-1 40 mg/m2 BID on D1–7. • ORR was 58.5 %, median PFS was 6.5 months, and median OS was 11.4 months. • Safety profiles were manageable. • NASOX may improve patient convenience while showing efficacy comparable to NALIRIFOX. [ABSTRACT FROM AUTHOR]

This open-label, phase I/II study evaluated safety and efficacy for first-line liposomal irinotecan + oxaliplatin + 5-fluorouracil + leucovorin (NALIRIFOX). Patients (aged ≥18 years) had locally advanced/metastatic pancreatic ductal adenocarcinoma (mPDAC), with an Eastern Cooperative Oncology Group performance status score of 0/1 and adequate organ function. Primary objectives were to determine the maximum tolerated dose (MTD) and to evaluate safety and tolerability. Treatment-emergent adverse events (TEAEs) were graded using National Cancer Institute Common Terminology Criteria for Adverse Events v4.03. Efficacy end-points included progression-free survival (PFS) and overall survival (OS); disease assessments used Response Evaluation Criteria in Solid Tumors 1.1. The MTD (liposomal irinotecan 50 mg/m2 [free-base equivalent], oxaliplatin 60 mg/m2, 5-fluorouracil 2400 mg/m2, leucovorin 400 mg/m2 every 2 weeks) was based on dose-limiting toxicities and cumulative safety data in four dose-exploration cohorts. The MTD was received by 32 of 56 patients, seven during dose exploration and 25 during dose expansion (median age 58.0 years [range, 39–76], 28 [87.5%] with metastatic disease at diagnosis [29 at study entry], and one receiving study treatment at data cutoff [26 February 2020]). Of these patients, 22 of 32 had grade ≥3 treatment-related TEAEs, most commonly neutropenia (31.3%), febrile neutropenia (12.5%) and hypokalaemia (12.5%); ten had serious treatment-related TEAEs; and three died from TEAEs considered unrelated to treatment. Median PFS and OS were 9.2 (95% CI: 7.69–11.96) and 12.6 (8.74–18.69) months, respectively. First-line NALIRIFOX for patients with locally advanced/mPDAC was generally manageable and tolerable. A randomised, controlled phase III study is underway. [Display omitted] • Patients with mPDAC received 1L NALIRIFOX every 2 weeks in this phase I/II trial. • MTD: liposomal irinotecan 50 mg/m2, OX 60 mg/m2, 5-FU 2400 mg/m2, LV 400 mg/m2. • No unexpected safety outcomes were apparent in the 32 patients receiving the MTD. • Median PFS was 9.2 months (95% CI: 7.69–11.96) and OS was 12.6 months (8.74–18.69). • Based on these findings, a phase 3 study of 1L NALIRIFOX vs gem/nab has started. [ABSTRACT FROM AUTHOR]

Chemotherapy dose modification to manage adverse events is commonplace in clinical practice. This exploratory analysis evaluates the impact of liposomal irinotecan dose modification on overall survival (OS) and progression-free survival (PFS) in the NAPOLI-1 clinical trial (NCT01494506). Analysis includes only patients enrolled under protocol version 2 who received at least the first 2 scheduled doses of study drug. Within the liposomal irinotecan +5 fluorouracil/leucovorin (5 FU/LV) arm, patients were grouped according to whether or not they had a dose modification within the first 6 weeks. Dose reduction was defined as any decrease from initial dose; dose delay was any dosing delay >3 days from target date. OS and PFS (Kaplan-Meier estimates) were compared within the liposomal irinotecan+5-FU/LV arm and between treatment arms. Unstratified hazard ratios (HRs) were calculated using Cox regression analysis. Of the 93 patients from the liposomal irinotecan+5 FU/LV arm included in the analysis, 53 experienced a dose modification (both delay and reduction, n = 30; delay only, n = 19; reduction only, n = 4). No apparent difference in median OS or PFS was observed between patients who did versus patients who did not have a dose modification (OS: 8.4 vs 6.7 months; HR, 0.89; PFS: 4.2 vs 3.1 months; HR, 0.74). An early dose reduction or delay of liposomal irinotecan+5-FU/LV in the first 6 weeks does not significantly impact OS or PFS compared to patients without dose modifications. This finding suggests that tolerability-guided dose modification of liposomal irinotecan does not adversely affect efficacy outcomes. [ABSTRACT FROM AUTHOR]

Pancreatic cancer is a highly lethal disease predominantly affecting older patients. Characterization of outcomes in these patients may help optimise treatment decisions. The global, phase 3 NAPOLI-1 trial (NCT01494506) demonstrated an overall survival (OS) benefit with liposomal irinotecan and 5-flurouracil/leucovorin (nal-IRI + 5-FU/LV) versus 5-FU/LV. This subgroup analysis explored impact of age on outcomes in NAPOLI-1 patients, and nal-IRI + 5-FU/LV efficacy and safety in older patients. This exploratory, post-hoc analysis of the NAPOLI-1 trial included patients aged ≥eighteen years (no upper limit) with metastatic pancreatic adenocarcinoma that had progressed on gemcitabine-based therapy. Patients were stratified by age (cut-offs at 65, 70, and 75 years); OS and progression-free survival (PFS) were estimated by Kaplan-Meier analysis. Of 417 randomized patients, 192 (46%), 110 (26%) and 43 (10%) were aged ≥65, ≥70 and ≥ 75 years, respectively. Mortality risk and risk of disease progression were similar in older and younger patients independent of treatment (HRs for median [m]OS/mPFS comparisons were 0.88/0.95 [<65 versus ≥65 years], 0.89/0.88 [<70 versus ≥70 years] and 1.04/0.98 [<75 versus ≥75 years]; P >.25). Reduced mortality/morbidity risk with nal-IRI + 5-FU/LV in older subgroups was in line with the wider population. No additional toxicities with nal-IRI + 5-FU/LV were observed in older patients: 86% of patients ≥75 years versus 69% <75 years required a dose delay or reduction due to toxicities (43% versus 32% dose reductions). Results suggest that older patients with metastatic pancreatic adenocarcinoma that progressed on prior gemcitabine-based treatment can benefit from second-line therapy, supporting nal-IRI + 5-FU/LV treatment in older patients. [ABSTRACT FROM AUTHOR]

Upfront surgery followed by postoperative treatment is a commonly adopted treatment for resectable pancreatic ductal adenocarcinoma (rPDAC). However, the risk of positive surgical margins, the poor recovery that often impairs postoperative treatments, and the risk of recurrence might limit the outcome of this strategy. This study evaluated the safety and the activity of liposomal irinotecan 50 mg/m2 + 5-fluorouracil 2400 mg/m2 + leucovorin 400 mg/m2 + oxaliplatin 60 mg/m2 (NALIRIFOX) in the perioperative treatment of patients with rPDAC. Eligible patients had a rPDAC with < 180° interface with major veins' wall. Patients received 3 cycles before and 3 cycles after resection with NALIRIFOX, days 1 and 15 of a 28-day cycle. The primary endpoint was the proportion of patients undergoing an R0 resection. 107 patients began preoperative treatment. Nine patients discontinued the treatment because of related or unrelated adverse events. Disease-control rate was 92.9%. 87 patients underwent surgical exploration, 11 had intraoperative evidence of metastatic disease, and 1 died for surgical complications. R0 resection rate was 65.3%. 49 patients completed the three postoperative cycles. The most common grade ≥ 3 adverse events were diarrhea and neutropenia. Median overall survival (OS) of ITT patients was 32.3 months (95% CI 27.8–44.3). Median disease-free and OS from surgery of resected patients were 19.3 (95% CI 12.6–34.1) and 40.3 months (95% CI 29-NA), respectively. Perioperative NALIRIFOX was manageable and active, and deserves further investigation in randomized trials comparing it with standard upfront surgery followed by adjuvant therapy. • Improvements in resectable pancreatic cancer (rPDAC) require active perioperative strategies. • nITRO, an investigator-initiated phase 2 study, evaluated NALIRIFOX in patients with rPDAC. • The rate of R0 resections – the primary endpoint – was high at 65.3%. • These results support perioperative NALIRIFOX in patients with rPDAC. [ABSTRACT FROM AUTHOR]

Abstract Background Liposomal irinotecan (nal-IRI) plus 5-fluorouracil and leucovorin (5-FU/LV) is approved for patients with metastatic pancreatic ductal adenocarcinoma (mPDAC) previously treated with gemcitabine-based therapy. This approval was based on significantly improved median overall survival compared with 5-FU/LV alone (6.1 vs 4.2 months; hazard ratio [HR], 0.67) in the global phase 3 NAPOLI-1 trial. Here, we report the final survival analysis and baseline characteristics associated with long-term survivors (survival of ≥1 year) in the NAPOLI-1 trial. Patients and methods Patients with mPDAC were randomised to receive nal-IRI + 5-FU/LV (n = 117), nal-IRI (n = 151), or 5-FU/LV (n = 149) for the first 4 weeks of 6-week cycles. Baseline characteristics and efficacy in the overall population were compared with those in patients who survived ≥1 year. Through 16th November 2015, 382 overall survival events had occurred. Results The overall survival advantage for nal-IRI+5-FU/LV vs 5-FU/LV was maintained from the original nanoliposomal irinotecan with fluorouracil and folinic acid in metastatic pancreatic cancer after previous gemcitabine-based therapy (NAPOLI-1) analysis (6.2 vs 4.2 months, respectively; HR, 0.75; 95% confidence interval: 0.57–0.99). Median progression-free survival, objective response rate and disease control rate also favoured nal-IRI+5-FU/LV therapy. Estimated one-year overall survival rates were 26% with nal-IRI+5-FU/LV and 16% with 5-FU/LV. Baseline characteristics associated with long-term survival in the nal-IRI+5-FU/LV arm were Karnofsky performance status ≥90, age ≤65 years, lower CA19-9 levels, neutrophil-to-lymphocyte ratio ≤5 and no liver metastases. No new safety concerns were detected. Conclusions The survival benefits of nal-IRI+5-FU/LV versus 5-FU/LV were maintained over an extended follow-up, and prognostic markers of survival ≥1 year were identified. Clinical trial registration number NCT01494506. Highlights • Final analysis of NAPOLI-1 trial of liposomal irinotecan confirmed primary analysis. • Longer overall survival in metastatic pancreatic cancer post–first line progression. • Long-term survival linked to higher performance score, younger age and lower CA19-9. • No new safety signals for liposomal irinotecan + 5-fluorouracil/leucovorin regimen. [ABSTRACT FROM AUTHOR]

Background PEP02 is a novel highly stable liposomal nanocarrier formulation of irinotecan. This randomized phase II study evaluated the efficacy and safety of single agent PEP02 compared with irinotecan or docetaxel in the second-line treatment of advanced oesophago-gastric (OG) cancer. Patients and methods Patients with locally advanced/metastatic disease who had failed one prior chemotherapy regimen were randomly assigned to PEP02 120 mg/m2, irinotecan 300 mg/m2 or docetaxel (Taxotere) 75 mg/m2 every 3 weeks. The primary end point was objective response rate (ORR). Simon's two-stage design was used and the ORR of interest was 20% (α = 0.05, type II error β = 0.10, null hypothesis of ORR was 5%). Results Forty-four patients per arm received treatment, and 124 were assessable for response. The ORR statistical threshold for the first stage was reached in all arms. In the intent-to-treat (ITT) population, ORRs were 13.6% (6/44), 6.8% (3/44) and 15.9% (7/44) in the PEP02, irinotecan and docetaxel arms, respectively. The median progression-free survival (PFS) and overall survival were similar between the trial arms. Commonest grade 3–4 adverse event reported was diarrhoea in the PEP02 and irinotecan groups (27.3% versus 18.2%). Conclusion The ORR associated with PEP02 was comparable with docetaxel and numerically greater than that of irinotecan. PEP02 warrants further evaluation in the advanced gastric cancer setting. [ABSTRACT FROM AUTHOR]