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Background: The phase III NAPOLI-3 trial, which upgraded FOLFIRINOX (leucovorin, fluorouracil, irinotecan and oxaliplatin) to NALIRIFOX (liposomal irinotecan, oxaliplatin, leucovorin, and fluorouracil), demonstrated the superiority of NALIRIFOX over GEMNABP (gemcitabine and nab-paclitaxel) as the first-line treatment for metastatic pancreatic ductal adenocarcinoma. The purpose of this study was to assess the cost-effectiveness of NALIRIFOX, FOLFIRINOX, and GEMNABP, and to simulate the price of liposomal irinotecan at which NALIRIFOX could achieve cost-effectiveness. Methods: A partitioned survival model was performed to evaluate the cost-effectiveness of NALIRIFOX, FOLFIRINOX and GEMNABP from the perspective of the Chinese healthcare system. Survival data was obtained from a recently published network meta-analysis (NMA). Drug prices were collected from the database of the Hunan Province Drug and Medical Consumables Procurement Management Subsystem. Other cost and utility values were sourced from established literature. Cumulative costs, LYs (life-years), quality-adjusted life years (QALYs), incremental cost-effectiveness ratios (ICERs), net monetary benefits (NMBs) and incremental net monetary benefits (INMBs) were the main outputs. Furthermore, the variations in ICER were analyzed as the price of liposomal irinotecan gradually decreased when comparing NALIRIFOX with FOLFIRINOX or GEMNABP. The robustness of the model was assessed by sensitivity analysis and scenario analysis. Results: At the willingness-to-pay (WTP) threshold of $38,223.34, GEMNABP was the favored treatment. NALIRIFOX was associated with the highest LYs, QALYs, and cost. The cost-effectiveness of NALIRIFOX would be obtained if the price of liposomal irinotecan was less than $3.36/mg and $2.08/mg compared to FOLFIRINOX and GEMNABP, respectively, without considering the patient assistance program (PAP). Sensitivity analysis and scenario analysis revealed that the results of the model were stable. Conclusion: From an economic standpoint, GEMNABP represents the favored choice in the prevailing market conditions among these three first-line combination chemotherapy regimens. The price simulation of liposomal irinotecan conducted in this study could provide valuable evidence for healthcare decision-making. Further evidence regarding the budget impact is still needed. [ABSTRACT FROM AUTHOR]

Pancreatic acinar cell carcinoma (PACC) represents a rare malignancy within the pancreatic tumor spectrum. Owing to its rarity, the establishment of a standardized chemotherapy regimen for patients presenting with either metastatic disease or recurrence after radical surgery remains elusive. Most previous studies and case reports have used gemcitabine-based and 5-fluorouracil-based regimens, however, no previous study has reported the use of liposomal irinotecan in combination with S-1. In this report, we present a patient with PACC who experienced disease progression with liver metastasis after radical tumor resection followed by chemoradiotherapy. The patient underwent second-line treatment with liposomal irinotecan in conjunction with S-1. Encouragingly, the patient has remained free of recurrence and progression during a follow-up period of 2 years and 3 months.

Background: Approximately half of the patients with advanced pancreatic ductal adenocarcinoma (PDAC) receive subsequent lines of chemotherapy. Recently, the liposomal irinotecan (nal-IRI) plus 5-fluorouracil/leucovorin (5-FU/LV) regimen is recommended as subsequent lines of chemotherapy. However, little is known about the predictive factors for the nal-IRI + 5-FU/LV regimen, especially in patients with previous irinotecan (IRI) exposure. Objectives: We investigated the predictive factors associated with nal-IRI + 5-FU/LV treatment in patients with PDAC. Design: Multicenter, retrospective cohort study. Methods: This study included patients with advanced PDAC who received the nal-IRI + 5-FU/LV regimen for palliative purposes. Results: Overall, 268 patients were treated with nal-IRI + 5-FU/LV. The median overall survival (OS) was 7.9 months (95% confidence interval (CI): 7.0–8.8), while the median progression-free survival (PFS) was 2.6 months (95% CI: 1.9–3.2). An albumin level of<4.0 g/dL, neutrophil-to-lymphocyte ratio (NLR) of ⩾3.5, liver or peritoneal metastasis, and a history of >3 lines of palliative chemotherapy were associated with worse OS. An NLR of ⩾3.5 and liver metastasis were significant predictive factors for worse PFS. Previous exposure to IRI was not a significant predictor. Patients without prior IRI (no-IRI) treatment showed relatively longer OS and PFS compared to IRI responders and nonresponders, but these differences were not significant when compared specifically to the responders (OS: 8.8 vs 8.1 months, p = 0.388; PFS: 3.6 vs 2.6 months, p = 0.126). Conclusion: An NLR of ⩾3.5 and liver metastasis were associated with worse PFS. Prior IRI exposure was not a significant predictive factor for OS and PFS, especially in IRI responders. [ABSTRACT FROM AUTHOR]

BackgroundThe phase III NAPOLI-3 trial, which upgraded FOLFIRINOX (leucovorin, fluorouracil, irinotecan and oxaliplatin) to NALIRIFOX (liposomal irinotecan, oxaliplatin, leucovorin, and fluorouracil), demonstrated the superiority of NALIRIFOX over GEMNABP (gemcitabine and nab-paclitaxel) as the first-line treatment for metastatic pancreatic ductal adenocarcinoma. The purpose of this study was to assess the cost-effectiveness of NALIRIFOX, FOLFIRINOX, and GEMNABP, and to simulate the price of liposomal irinotecan at which NALIRIFOX could achieve cost-effectiveness.MethodsA partitioned survival model was performed to evaluate the cost-effectiveness of NALIRIFOX, FOLFIRINOX and GEMNABP from the perspective of the Chinese healthcare system. Survival data was obtained from a recently published network meta-analysis (NMA). Drug prices were collected from the database of the Hunan Province Drug and Medical Consumables Procurement Management Subsystem. Other cost and utility values were sourced from established literature. Cumulative costs, LYs (life-years), quality-adjusted life years (QALYs), incremental cost-effectiveness ratios (ICERs), net monetary benefits (NMBs) and incremental net monetary benefits (INMBs) were the main outputs. Furthermore, the variations in ICER were analyzed as the price of liposomal irinotecan gradually decreased when comparing NALIRIFOX with FOLFIRINOX or GEMNABP. The robustness of the model was assessed by sensitivity analysis and scenario analysis.ResultsAt the willingness-to-pay (WTP) threshold of $38,223.34, GEMNABP was the favored treatment. NALIRIFOX was associated with the highest LYs, QALYs, and cost. The cost-effectiveness of NALIRIFOX would be obtained if the price of liposomal irinotecan was less than $3.36/mg and $2.08/mg compared to FOLFIRINOX and GEMNABP, respectively, without considering the patient assistance program (PAP). Sensitivity analysis and scenario analysis revealed that the results of the model were stable.ConclusionFrom an economic standpoint, GEMNABP represents the favored choice in the prevailing market conditions among these three first-line combination chemotherapy regimens. The price simulation of liposomal irinotecan conducted in this study could provide valuable evidence for healthcare decision-making. Further evidence regarding the budget impact is still needed.

Pancreatic acinar cell carcinoma (PACC) represents a rare malignancy within the pancreatic tumor spectrum. Owing to its rarity, the establishment of a standardized chemotherapy regimen for patients presenting with either metastatic disease or recurrence after radical surgery remains elusive. Most previous studies and case reports have used gemcitabine-based and 5-fluorouracil-based regimens, however, no previous study has reported the use of liposomal irinotecan in combination with S-1. In this report, we present a patient with PACC who experienced disease progression with liver metastasis after radical tumor resection followed by chemoradiotherapy. The patient underwent second-line treatment with liposomal irinotecan in conjunction with S-1. Encouragingly, the patient has remained free of recurrence and progression during a follow-up period of 2 years and 3 months. [ABSTRACT FROM AUTHOR]

Summary: Background: This was a multicenter, single-arm dose-ranging phase 2 study aimed to assess the efficacy and safety of LY01610, a liposomal irinotecan, at various doses for patients with relapsed small cell lung cancer (SCLC). Methods: This study (NCT04381910) enrolled patients with relapsed SCLC at 10 hospitals across China, who have failed with previous platinum-based treatments. LY01610 was administered at doses of 60 mg/m2, 80 mg/m2, and 100 mg/m2. Primary endpoints were investigator-assessed objective response rate (ORR) and investigator-assessed duration of response (DoR). Secondary endpoints included investigator-assessed disease control rate (DCR), investigator-assessed progression-free survival (PFS), overall survival (OS), and safety. Findings: From September 3, 2020 to March 3, 2022, a total of 66 patients were enrolled, with 6, 30, and 30 allocated to the 60 mg/m2, 80 mg/m2, and 100 mg/m2 dose groups, respectively, with 68% (45/66) having a chemotherapy-free interval

The approval of novel therapeutic agents remains widely reliant on evidence derived from large phase III randomized controlled trials. Liposomal irinotecan (ONIVYDE®) stands out as the only drug that has demonstrated improved survival both as a first-line therapy in combination with oxaliplatin and 5-fluorouracil/leucovorin (5FU/LV) (NALIRIFOX) compared to the standard gemcitabine plus nab-paclitaxel in the NAPOLI3 trial, and as a second-line treatment in combination with 5FU/LV compared to the standard 5FU/LV in the NAPOLI1 trial. However, just as the white bear of the Dostoevsky's paradox, the judgment of these results is invariably distracted by the intrusive thought of how different they might be if compared to similar regimens containing standard-free irinotecan as FOLFIRINOX or FOLFIRI, respectively. Here, we present and thoroughly discuss the evidence encompassing the pharmacologic, preclinical, and clinical development of liposomal irinotecan that can dispel any intrusive thoughts and foster a rational and well-considered judgment of this agent and its potential integration into the therapeutic strategies for pancreatic ductal adenocarcinoma. [ABSTRACT FROM AUTHOR]

PurposeMetastatic breast cancer (mBC) remains incurable and is associated with low survival rates. This study assessed the efficacy and safety of liposomal irinotecan in heavily pretreated patients with mBC, with or without active brain metastases (BM).MethodsFollowing the dose escalation phase and determination of recommended phase 2 dose, the expansion phase of this phase I, open-label, non-randomized study, assigned adult women to cohorts based on mBC subtype: cohort 1, hormone receptor +/human epidermal growth factor receptor 2-; cohort 2, triple-negative breast cancer; or cohort 3, any mBC subtype with active BM. Patients received liposomal irinotecan 50 or 70 mg/m2 free base every 2 weeks. Here, we report secondary outcomes including best overall response (BOR), objective response rate (ORR), and treatment-emergent adverse events (TEAEs).ResultsFor non-central nervous system (non-CNS) disease across all cohorts (intent-to-treat population, N = 29), the ORR was 34.5% (95% confidence interval: 17.94-54.33), with a BOR of partial response in 10 patients (34.5%), stable disease in five (17.2%), progressive disease in 10 (34.5%); four patients were unevaluable (13.8%). The ORR for the CNS cohort was 30.0% (95% confidence interval: 6.67-65.25) using modified Response Evaluation Criteria in Solid Tumors. Common grade 3 or higher TEAEs were diarrhea (27.6%), nausea (17.2%), fatigue (13.8%), asthenia (10.3%), and hypokalemia (10.3%). Serious treatment-related TEAEs were reported in six patients (20.7%). No treatment-related TEAEs resulted in death.ConclusionsLiposomal irinotecan monotherapy demonstrated antitumor activity in heavily pretreated patients with mBC, with or without BM. The observed safety profile was consistent with that in previous studies.Clinical trial registrationTrial registration ID NCT01770353.

BackgroundThe NAPOLI-1 trial demonstrated that liposomal irinotecan in combination with fluorouracil (5-FU) and leucovorin (LV) prolonged survival with a manageable safety profile in patients with metastatic pancreatic ductal adenocarcinoma (mPDAC) previously treated with gemcitabine-based therapy. Real-world data on clinical outcomes associated with liposomal irinotecan in NAPOLI-1-based regimens is needed to further substantiate this.MethodsThis real-world, retrospective chart review study included patients with mPDAC who received NAPOLI-1-based regimens from six academic centers in the United States. Liposomal irinotecan initiation defined the index date. Overall survival (OS) and progression-free survival (PFS) were assessed with Kaplan-Meier methodology.ResultsThere were 374 patients evaluated; median age was 68 years, and 51% were female. Among 326 patients with baseline ECOG information, approximately 74% had ECOG score

For patients with localized pancreatic cancer with minimal vascular involvement, optimal survivability requires a multidisciplinary approach of surgical resection and systemic chemotherapy. FOLFIRINOX is a combination chemotherapy regimen that offers promising results in the perioperative and metastatic settings; however, it can cause significant adverse effects. Such toxicity can negatively impact some patients, resulting in chemotherapy discontinuation or surgical unsuitability. In an effort to reduce toxicities and optimize outcomes, this investigation explores the safety and feasibility of substituting liposomal irinotecan (nal-IRI) for nonliposomal irinotecan to improve tumor drug delivery and potentially reduce toxicity. This regimen, NALIRIFOX, has the potential to be both safer and more effective when administered in the preoperative setting. For patients with pancreatic cancer with little to no cancer near the blood vessels, the best life expectancy usually requires surgery and chemotherapy. FOLFIRINOX is a chemotherapy medicine that offers promising results for both patients getting surgery and for patients with widespread disease. However, it can cause harmful side effects. The side effects can be so bad that the chemotherapy has to be stopped or that surgery is no longer possible. In order to reduce the harmful side effects and improve outcomes, this investigation looks into the safety and practicality of using a different version of one of the medicines. The different version hopes to improve drug delivery and reduce harmful side effects. This regimen, NALIRIFOX, can be safer and more effective in patients awaiting surgery. Clinical Trial Registration: UF-STO-PANC-004 (NCT03483038) (ClinicalTrials.gov) NALIRIFOX, a Phase II clinical trial for the treatment of resectable and borderline resectable pancreatic cancer. The regimen includes novel liposomal irinotecan in combination with 5-fluorouracil, leucovorin and oxaliplatin. Enrolling in multiple sites (NCT03483038). [ABSTRACT FROM AUTHOR]

Abstract Introduction Liposomal irinotecan promotes controlled sustained release of irinotecan (CPT-11), therefore, we hypothesize that the therapeutic index (quantitative measurement of the relative efficacy/safety ratio of a drug) will be higher for liposomal than non-liposomal irinotecan. Methods We compared the therapeutic indexes of liposomal and non-liposomal irinotecan in mice bearing subcutaneous patient-derived xenograft (PDX) pancreatic tumors under dosing regimens approximating the clinical setting. Following preliminary drug sensitivity/antitumor activity analyses on three PDX tumor models, one model was selected for analyses of efficacy, biomarker, toxicology, pharmacokinetics in mice receiving liposomal irinotecan (2.5, 10, 50 mg/kg/week) or non-liposomal irinotecan (10, 25, 50 mg/kg/week). The maximum tolerated dose (MTD) for each treatment was 50 mg/kg/week. Results Using the selected IM-PAN-001 model at the MTD (both treatments, 50 mg/kg/week), antitumor activity, phospho-histone gamma-H2AX protein staining in cancer cell nuclei, histological tumor regression, and plasma levels of CPT-11 and its active metabolite SN-38 after 24 h were greater with liposomal than non-liposomal irinotecan, but tumor SN-38 levels were similar. At the lowest doses assessed, antitumor activity, histological tumor regression, and jejunum and bone marrow toxicity were similar. Based on these findings, liposomal and non-liposomal irinotecan had therapeutic indexes of 20 and 5, respectively. Conclusion This non-clinical study showed a fourfold broader therapeutic index with liposomal than non-liposomal irinotecan in mice bearing IM-PAN-001 PDX pancreatic tumors, even at optimal dosing for the two drugs. These findings support the clinical benefit observed with liposomal irinotecan in patients with pancreatic cancer.

Abstract Background Pancreatic cancer has one of the worst prognoses of any all cancers. 5-FU/leucovorin + irinotecan + oxaliplatin (FOLFIRINOX), gemcitabine (GEM) plus nab-paclitaxel regimens have been recognized as global-standard, first-line treatments for patients with advanced pancreatic cancer. The liposomal irinotecan (nal-IRI) + 5-FU/LV regimen is now included in treatment guidelines as a recommended and approved option for use in patients with metastatic pancreatic cancer that has progressed after GEM-based therapy and who have a suitable performance status and comorbidity profile. There is no report that nal-IRI + 5-FU/LV regimen was significantly effective, and we will report it because we experienced this time. Case presentation A 69-year-old man presented with epigastric pain, and a contrast computed tomography (CT) revealed an enhanced mass lesion measuring 33 × 27 mm on the pancreatic body with encasement of the common hepatic artery (CHA) and the splenic vein. An endoscopic ultrasound-guided fine needle aspiration was performed and demonstrated cytology consistent with adenocarcinoma. Therefore, we diagnosed the patient with unresectable locally advanced pancreatic cancer. The patient received the GEM and S-1 regimen; however, the adverse event was relatively severe. Then, 11 cycles of nal-IRI + 5-FU/LV regimen were administered. A CT scan revealed that the tumor had shrunk to 18 × 7 mm in diameter with encasement of the CHA. The encasement of the splenic vein had disappeared, without any distant metastases. From this post-chemotherapy evaluation and intraoperative frozen section of around the celiac artery, gastroduodenal artery and pancreas stump confirmed absence of tumor cells, we performed distal pancreatectomy with celiac axis resection. A histological examination of the surgical specimen revealed no evidence of residual adenocarcinoma, consistent with a pathological complete response to treatment. Conclusions We present the first case of a pathological complete response with nal-IRI + 5-FU/LV for unresectable, locally advanced pancreatic cancer. In the future, nal-IRI may become a key drug for pancreatic cancer treatment.

BackgroundThe efficacy of combination chemotherapy beyond the first-line setting remains modest in patients with advanced pancreatic adenocarcinoma (PAC). Evidence from recent clinical studies has shown that liposomal irinotecan (nal-IRI) plus 5-fluorouracil (5-FU) and leucovorin (LV) resulted in survival benefits in patients with advanced pancreatic adenocarcinoma (APAC) after progression on gemcitabine-based treatment. However, the survival benefits of nal-IRI in the third and later lines, in which limited options are available, have yet to be extensively studied. Also, some studies have shown conflicting results regarding the impact of prior treatment with conventional IRI on patient outcomes following treatment with nal-IRI. Therefore, this real-world study aimed to evaluate the efficacy and safety of nal-IRI plus 5FU-LV in advanced PAC patients who progressed on conventional IRI-containing regimens.MethodsA retrospective chart review was conducted between November 2016 to December 2022 on 30 patients diagnosed with advanced PAC who completed at least one cycle of nal-IRI plus 5-FU- LV and were previously treated with conventional IRI. Data regarding survival outcomes were retrieved.ResultsThirty patients met the inclusion criteria. Overall, 76.7% of the patients received at least two lines of therapy prior to nal-IRI. The median overall duration of nal-IRI treatment was 2.0 months (IQR: 1.3 – 3.9 months). One patient (3.3%) had a partial response, and seven patients (23.3%) had stable disease as their best response. The median progression-free survival (PFS) was 1.9 months (95% CI 1.6 - 2.0) and the 6-month PFS rate was 20.0%. The median overall survival (OS) was 5.0 months (95% CI 3.4 – 7.0), and the 6-month OS rate was 36.7%. An interval between conventional IRI and nal-IRI ≥5.5 months was significantly associated with prolonged OS of 10.2 months (95% CI 3.3 – 12.1) versus 4.3 months (95% CI 2.1 – 5.9; p =0.003). Ten patients (33.3%) experienced grade 3 adverse events, most commonly nausea, fatigue, diarrhea, and non-neutropenic fever.ConclusionNal-IRI plus 5FU/LV had modest survival benefits and an acceptable safety profile in patients with prior conventional IRI. A longer interval between conventional IRI and nal-IRI was associated with increased survival outcomes.

Summary: Background: The prognosis for patients with poorly-differentiated extra-pulmonary neuroendocrine carcinoma (PD-EP-NEC) is poor. A recognised first-line (1L) treatment for advanced disease is etoposide/platinum-based chemotherapy with no standard second-line (2L) treatment. Methods: Patients with histologically-confirmed PD-EP-NEC (Ki-67 > 20%; Grade 3) received IV liposomal irinotecan (nal-IRI) (70 mg/m2 free base)/5-FU (2400 mg/m2)/folinic acid, Q14 days (ARM A), or IV docetaxel (75 mg/m2), Q21 days (ARM B), as 2L therapy. Primary endpoint was 6-month progression-free survival (PFS) rate (80% power to demonstrate one-sided 95% lower confidence interval excluded 15% (target level of efficacy: 30%)). Secondary endpoints: objective response rate (ORR), median PFS, overall survival (OS), toxicity and patient-reported quality-of-life (QoL) (ClinicalTrials.gov: NCT03837977). Findings: Of 58 patients (29 each arm); 57% male, 90% ECOG PS 0/1, 10% PS 2, 89.7% Ki-67 ≥ 55%, primary site: 70.7%-gastrointestinal, 18.9%-other, 10.3%-unknown, 91.4%/6.9%/1.7% were resistant/sensitive/intolerant to 1L platinum-based treatment, respectively. The primary end-point of 6-month PFS rate was met by ARM A: 29.6% (lower 95% Confidence-Limit (CL) 15.7), but not by ARM B: 13.8% (lower 95%CL:4.9). ORR, median PFS and OS were 11.1% (95%CI:2.4–29.2) and 10.3% (95%CI:2.2–27.4%); 3 months (95%CI:2–6) and 2 months (95%CI:2-2); and 6 months (95%CI:3–10) and 6 months (95%CI:3–9) in ARMS A and B, respectively. Adverse events ≥ grade 3 occurred in 51.7% and 55.2% (1 and 6 discontinuations due to toxicity in ARMS A and B), respectively. QoL was maintained in ARM A, but not ARM B. Interpretation: nal-IRI/5-FU/folinic acid, but not docetaxel, met the primary endpoint, with manageable toxicity and maintained QoL, with no difference in OS. ORR and median PFS were similar in both arms. This study provides prospective efficacy, toxicity and QoL data in the 2L setting in a disease group of unmet need, and represents some of the strongest evidence available to recommend systemic treatment to these patients. Funding: Servier.

Introduction: Combination therapeutic mode is likely to be the key to enhance the efficacy of immunotherapy in a wider range of cancer patients. Herein, we conducted an open-label, single-arm, multicenter, phase II clinical trial that enrolled patients with advanced solid tumors who had progressed after standard treatments. Methods: Radiotherapy of 24 Gy/3 fractions/3-10 days was given to the targeted lesions. Liposomal irinotecan (80mg/m², dose could be adjusted to 60 mg/m² for intolerable cases) was intravenously (IV) administered once within 48 hours after radiotherapy. Then, camrelizumab (200mg IV, q3w) and anti-angiogenic drugs were given regularly until disease progression. The primary endpoint was objective response rate (ORR) in the target lesions evaluated by investigators per RECIST 1.1. The secondary endpoints were disease control rate (DCR) and treatment-related adverse events (TRAEs). Results: Between November 2020 and June 2022, 60 patients were enrolled. The median follow-up was 9.0 months (95% confidence interval (CI) 5.5-12.5). Of 52 evaluable patients, the overall ORR and DCR were 34.6% and 82.7%, respectively. Fifty patients with target lesions were evaluable, the ORR and DCR of the target lesions were 35.3% and 82.4%, respectively. The median progression-free survival was 5.3 months (95% CI 3.6, 6.2), and the median overall survival was not reached. TRAEs (all grades) occurred in 55 (91.7%) patients. The most common grade 3-4 TRAEs were lymphopenia (31.7%), anemia (10.0%), and leukopenia (10.0%). Conclusion: The combination of radiotherapy, liposomal irinotecan, camrelizumab, and anti-angiogenesis therapy demonstrated promising antitumor activity and well tolerance in various advanced solid tumors. [ABSTRACT FROM AUTHOR]

Introduction: Liposomal irinotecan promotes controlled sustained release of irinotecan (CPT-11), therefore, we hypothesize that the therapeutic index (quantitative measurement of the relative efficacy/safety ratio of a drug) will be higher for liposomal than non-liposomal irinotecan. Methods: We compared the therapeutic indexes of liposomal and non-liposomal irinotecan in mice bearing subcutaneous patient-derived xenograft (PDX) pancreatic tumors under dosing regimens approximating the clinical setting. Following preliminary drug sensitivity/antitumor activity analyses on three PDX tumor models, one model was selected for analyses of efficacy, biomarker, toxicology, pharmacokinetics in mice receiving liposomal irinotecan (2.5, 10, 50 mg/kg/week) or non-liposomal irinotecan (10, 25, 50 mg/kg/week). The maximum tolerated dose (MTD) for each treatment was 50 mg/kg/week. Results: Using the selected IM-PAN-001 model at the MTD (both treatments, 50 mg/kg/week), antitumor activity, phospho-histone gamma-H2AX protein staining in cancer cell nuclei, histological tumor regression, and plasma levels of CPT-11 and its active metabolite SN-38 after 24 h were greater with liposomal than non-liposomal irinotecan, but tumor SN-38 levels were similar. At the lowest doses assessed, antitumor activity, histological tumor regression, and jejunum and bone marrow toxicity were similar. Based on these findings, liposomal and non-liposomal irinotecan had therapeutic indexes of 20 and 5, respectively. Conclusion: This non-clinical study showed a fourfold broader therapeutic index with liposomal than non-liposomal irinotecan in mice bearing IM-PAN-001 PDX pancreatic tumors, even at optimal dosing for the two drugs. These findings support the clinical benefit observed with liposomal irinotecan in patients with pancreatic cancer. [ABSTRACT FROM AUTHOR]

Approximately 80% of pancreatic cancer is diagnosed at an advanced stage, due to lack of or vague symptoms when the cancer is still localized, leading to a high mortality rate. Known risk factors for developing pancreatic cancer are family history, obesity, type 2 diabetes, and alcohol and tobacco use. There has been a remarkable development in diagnosis modalities and molecular testing, but early detection is still infrequent. The majority of clinical trials have not shown significant efficacy in pancreatic cancer, and treatment strategy remains limited. Additional prognostic factors should be highlighted to obtain appropriate treatment options, including precision medicine, and improve survival outcomes. After the PRODIGE study in 2011 and the MPAC trial in 2013, a new drug (liposomal irinotecan; Onivyde ®) appeared in the strategy, especially after failure of gemcitabine-based treatment. In 2016, the NAPOLI-1 trial showed evidence of the efficacy of the liposomal irinotecan combination (liposomal irinotecan +5-fluorouracile + folinic acid); now, it is considered the standard treatment for relapsing patients. Since NAPOLI-1, real-world data have provided similar results. Herein, we report the story of a 61-year-old woman who was treated with liposomal irinotecan combination (nal-IRI/5-FU/LV) for 8 months with good surgical response, but treatment was discontinued due to economic burden. After the start of treatment (or 1? cycle of liposomal irinotecan treatment), the patient was in a better condition. The liver metastases had disappeared. The combination with liposomal irinotecan was re-administered with patient’s approval. Upon rechallenge with the liposomal irinotecan combination, she showed a partial response, and the treatment was given for 7 months. In this report, we tried to identify the prognostic factors leading to the efficacy of the liposomal irinotecan combination.

Background: Pancreatic cancer has one of the worst prognoses of any all cancers. 5-FU/leucovorin + irinotecan + oxaliplatin (FOLFIRINOX), gemcitabine (GEM) plus nab-paclitaxel regimens have been recognized as global-standard, first-line treatments for patients with advanced pancreatic cancer. The liposomal irinotecan (nal-IRI) + 5-FU/LV regimen is now included in treatment guidelines as a recommended and approved option for use in patients with metastatic pancreatic cancer that has progressed after GEM-based therapy and who have a suitable performance status and comorbidity profile. There is no report that nal-IRI + 5-FU/LV regimen was significantly effective, and we will report it because we experienced this time. Case presentation: A 69-year-old man presented with epigastric pain, and a contrast computed tomography (CT) revealed an enhanced mass lesion measuring 33 × 27 mm on the pancreatic body with encasement of the common hepatic artery (CHA) and the splenic vein. An endoscopic ultrasound-guided fine needle aspiration was performed and demonstrated cytology consistent with adenocarcinoma. Therefore, we diagnosed the patient with unresectable locally advanced pancreatic cancer. The patient received the GEM and S-1 regimen; however, the adverse event was relatively severe. Then, 11 cycles of nal-IRI + 5-FU/LV regimen were administered. A CT scan revealed that the tumor had shrunk to 18 × 7 mm in diameter with encasement of the CHA. The encasement of the splenic vein had disappeared, without any distant metastases. From this post-chemotherapy evaluation and intraoperative frozen section of around the celiac artery, gastroduodenal artery and pancreas stump confirmed absence of tumor cells, we performed distal pancreatectomy with celiac axis resection. A histological examination of the surgical specimen revealed no evidence of residual adenocarcinoma, consistent with a pathological complete response to treatment. Conclusions: We present the first case of a pathological complete response with nal-IRI + 5-FU/LV for unresectable, locally advanced pancreatic cancer. In the future, nal-IRI may become a key drug for pancreatic cancer treatment. [ABSTRACT FROM AUTHOR]

Abstract Background According to the NAPOLI-1 trial, nanoliposomal irinotecan (nal-IRI) plus fluorouracil/folinic acid (5-FU/LV) showed improved overall survival compared to fluorouracil alone for patients with metastatic pancreatic cancer who were previously treated with gemcitabine-based therapy. In that trial, Asian patients had frequent dose modification due to haematological toxicity. There has been limited information on the clinical benefits and toxicity of this regimen in real-world settings. In this study, we assessed real-world experience of nal-IRI plus 5-FU/LV in patients with advanced pancreatic cancer after gemcitabine failure. Methods We conducted a single institution, retrospective analysis of response, survival and safety in patients who had been treated with nal-IRI with 5-FU/LV. Patients with metastatic pancreatic ductal adenocarcinoma previously treated with gemcitabine-based therapy received nal-IRI (80 mg/m2) with 5-FU/LV every 2 weeks. Kaplan-Meier analysis was performed to obtain median progression free survival and median overall survival. The hazard ratio and 95% confidence interval (CI) were estimated using a stratified Cox regression model. A multivariate Cox proportional hazards regression model was used to identify the effects of clinical factors. Results Fifty-one patients received nal-IRI plus 5-FU/LV between January 2015 and December 2020. The median age was 67 years, and males were 58.8%. A total of 40 (78.4%) and 11 (21.6%) patients had received one and two lines of prior chemotherapy before enrollment, respectively. Median progression-free survival was 2.8 months (95% CI 1.8–3.7) and median overall survival was 7.0 months (95% CI 6.0–7.9). Chemotherapy doses were reduced or delayed in 33 (64.7%) patients during the first 6 weeks and median relative dose intensity was 0.87. Thirty-six (70.6%) patients experienced grade 3 or 4 adverse events, most commonly neutropenia (58.8%). Most non-haematologic adverse events were under grade 2. Since the start of first-line chemotherapy, median overall survival was 16.3 months (95% CI 14.1–18.4). Conclusions Nal-IRI plus 5-FU/LV seems to be effective, with manageable toxicities, following gemcitabine-based treatment in patients with metastatic pancreatic ductal adenocarcinoma. Nal-IRI plus 5-FU/LV following gemcitabine with nab-paclitaxel is a feasible sequential treatment option in patients with metastatic pancreatic cancer. Trial registration Retrospectively registered.

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]

Abstract Background This multicentre, open‐label study evaluated the efficacy and safety of antiprogrammed death ligand 1 antibody SHR‐1316 plus liposomal irinotecan and 5‐fluorouracil as the first‐line treatment for patients with advanced esophageal squamous cell carcinoma (ESCC). Methods Eligible patients received SHR‐1316 (10 mg/kg), liposomal irinotecan (60 mg/m2 for the first cycle, 80 mg/m2 thereafter), and 5‐fluorouracil (2400 mg/m2) every 14 days until disease progression, intolerable toxicity or withdrawal of consent. The primary endpoint was progression‐free survival (PFS). Secondary endpoints were objective response rate (ORR), disease control rate (DCR), overall survival (OS), and safety. Results We enrolled 23 patients between 11 March 2019 and 31 May 2019. The median follow‐up duration was 15.2 months (95% CI 14.2–16.2). The median PFS was 8.5 months (95% CI 1.2–15.8), and ORR and DCR were 52.2% (95% CI 30.1–74.3) and 73.9% (95% CI 54.5–93.3), respectively. The median OS was 11.6 months (95% CI 6.7–16.6). The most common treatment‐related grade 3–4 adverse events (AEs) were neutropenia (17.4%), nausea (13.0%), and anorexia (13.0%). Treatment‐related serious AEs occurred in two patients. No treatment‐related deaths occurred. Conclusions SHR‐1316 plus liposomal irinotecan and 5‐fluorouracil has a promising efficacy and manageable safety profile, and could be a new first‐line treatment approach for patients with unresectable locally advanced or distant metastatic ESCC.

Background: Cholangiocarcinoma is a kind of malignant tumor that originates in the epithelium of the biliary tract. Although there are several options for second-line treatment for patients without specific genetic mutations, the overall treatment efficacy is disappointing. Second-line treatment which is composed of liposomal irinotecan plus fluorouracil and leucovorin significantly improved the treatment efficacy for advanced biliary tract cancer and extended patient survival. This study aims to evaluate the efficacy and safety of the combination of cadonilimab with liposomal irinotecan plus fluorouracil and leucovorin for advanced biliary tract cancer., Objectives: The primary objective of this study is to determine the objective response rate. The second objectives of this study are overall survival, progression-free survival, disease control rate, and adverse event incidence rate., Design: The study is a single-arm, prospective phase II clinical trial. In all, 51 patients who are diagnosed with locally advanced or metastatic bile tract cancer will be enrolled., Methods and Analysis: Eligible participants will receive cadonilimab at a dosage of 6 mg/kg on day 1 of each 21-day cycle combined with intravenous liposomal irinotecan at a dosage of 70 mg/m 2 for 90 min on day 1 plus leucovorin at a dosage of 400 mg/m 2 for 30 min on day 1 and fluorouracil at a dosage of 400 mg/m 2 for 46 h every 2 weeks., Discussion: Previous studies have suggested that there is a synergistic effect between the two treatment modalities. However, the potential of cadonilimab in bile tract cancer has not been explored. Hence, this trial is the first to investigate its efficacy and toxicity. In addition, the trial is also willing to explore potential biomarkers in patients with locally advanced and metastatic bile tract cancer., Trial Registration: This study was registered on ClinicalTrials.gov with NCT06438822., Ethics: This study protocol and amendments have been approved by the Ethics Committee of West China Hospital (2024(791))., Competing Interests: The authors declare that there is no conflict of interest., (© The Author(s), 2024.)

Purpose: While fluoropyrimidine-based chemotherapy regimens are recommended second-line treatment for patients with advanced biliary tract cancer (BTC), there have been no studies comparing different regimens head-to-head., Materials and Methods: We performed individual patient-level meta-analysis based on data from the intention-to-treat population of the phase 2b NIFTY trial (liposomal irinotecan [nal-IRI] plus fluorouracil and leucovorin [5-FU/LV] vs. 5-FU/LV; NCT03542508) and the phase 2 FIReFOX trial (modified oxaliplatin plus 5-FU/LV [mFOLFOX] vs. modified irinotecan plus 5-FU/LV [mFOLFIRI]; NCT03464968). Pairwise log-rank tests and multivariable analysis using Cox proportional hazards modeling with shared frailty to account for the trial's effect were used to compare overall survival (OS) between regimens., Results: A total of 277 patients were included. The nal-IRI plus 5-FU/LV group (n=88) showed significantly better OS compared to the mFOLFOX group (n=49, pairwise log-rank, p=0.02), and mFOLFIRI group (n=50, p =0.03). Multivariable analysis showed consistent trends in OS with adjusted hazard ratios of 1.39 (mFOLFOX vs nal-IRI plus 5-FU/LV, 95% CI 0.93-2.07, p=0.11) and 1.36 (mFOLFIRI vs nal-IRI plus 5-FU/LV, 95% CI 0.92-2.03, p=0.13), respectively. Compared to the 5-FU/LV group, the mFOLFOX group and the mFOLFIRI group did not show differences in terms of OS (pairwise log-rank p=0.83 and p=0.58, respectively). The nal-IRI plus 5-FU/LV group experienced more frequent diarrhea, while the mFOLFOX group experienced peripheral neuropathy., Conclusion: Nal-IRI plus 5-FU/LV showed favorable survival outcomes compared to mFOLFOX, mFOLFIRI, or 5-FU/LV. The safety profiles of these regimens should be considered along with efficacy.

Biliary tract cancers (BTC) are rare but aggressive. Due to limited anti-tumor effects of current second- and later-line treatment regimens, novel treatment options are required. Nanoliposomal irinotecan in combination with leucovorin and 5-fluorouracil (FOLFnal-IRI) achieved promising results as a second-line treatment in patients with pancreatic cancer, warranting further investigation in BTC. In the present study, a retrospective analysis of patients receiving FOLFnal-IRI after initial platinum-based chemotherapy for advanced BTC between January 2016 and August 2020 at the University Hospital Cologne (Cologne, Germany) was performed. A total of 11 patients were identified who met the inclusion criteria. A total of 4 patients (36.4%) were female and the median age was 54 years. The proportion of patients suffering from gallbladder carcinoma, intrahepatic and extrahepatic cholangiocarcinoma was 18.2, 63.6 and 9.1%, respectively. Furthermore, 7 patients (63.6%) received FOLFnal-IRI as their second-, 3 (27.3%) as third- and one (9.1%) as their fourth-line therapy. The disease control rate was 54.5% and 3 grade III toxicities were recorded. Progression-free survival and overall survival (OS) after initiation of FOLFnal-IRI was 5.1 and 12.4 months, respectively. OS after initial diagnosis was 24.7 months. FOLFnal-IRI demonstrated promising antitumor potential with an acceptable safety profile as a subsequent therapy regimen in advanced biliary tract malignancies. Further randomized controlled trials of its value as a treatment option for BTC appear justified. [ABSTRACT FROM AUTHOR]

Background: Liposomal irinotecan (nal-IRI) plus 5-fluorouracil and leucovorin (5-FU/LV) is currently the standard second-line treatment for patients with pancreatic ductal adenocarcinoma (PDAC) after previous failed gemcitabine-based therapy. This population-based study aimed to evaluate the efficacy and safety of nal-IRI + 5-FU/LV and the association of pre-emptive nal-IRI dosing with treatment outcomes in patients with PDAC. Methods: We retrospectively enrolled a total of 667 consecutive patients with PDAC who received nal-IRI plus 5-FU/LV treatment between August 2018 and November 2020 at 9 medical centers in Taiwan. Patients were allocated into groups according to pre-emptive nal-IRI dosing (⩾75%, 50–74%, <50%) for comparison of treatment efficacy and safety. Results: The median overall survival (OS) and time to treatment failure (TTF) were 5.9 months [95% confidence interval (CI), 5.3–6.5] and 2.8 months (95% CI, 2.6–3.0), respectively. The median OS was 6.5 months (95% CI, 5.7–6.7), 5.0 months (95% CI, 3.4–6.5), and 4.1 months (95% CI, 2.7–5.6), respectively, among the ⩾75%, 50–74%, and <50% pre-emptive nal-IRI dosing groups, whereas the median TTF of the three groups was 3.0 months (95% CI, 2.6–3.4), 2.6 months (95% CI, 2.3–2.9), and 1.9 months (95% CI, 1.6–2.2), respectively. Pre-emptive nal-IRI dosing <50% was an independent negative prognostic factor for OS and TTF in multivariate analyses. The most common severe adverse events were neutropenia (22.9%), anemia (21.1%), and hypokalemia (15.4%). Patients in the <50% pre-emptive nal-IRI dosing group had a significantly lower incidence of neutropenia and non-neutropenic infection than those in the other groups. Conclusion: Our results support the use of nal-IRI + 5-FU/LV as standard clinical practice for treating patients with PDAC based on this large population-based study. Our findings encourage physicians to provide adequate doses of nal-IRI in order to achieve better outcomes without compromising safety profiles. [ABSTRACT FROM AUTHOR]

Background: According to the NAPOLI-1 trial, nanoliposomal irinotecan (nal-IRI) plus fluorouracil/folinic acid (5-FU/LV) showed improved overall survival compared to fluorouracil alone for patients with metastatic pancreatic cancer who were previously treated with gemcitabine-based therapy. In that trial, Asian patients had frequent dose modification due to haematological toxicity. There has been limited information on the clinical benefits and toxicity of this regimen in real-world settings. In this study, we assessed real-world experience of nal-IRI plus 5-FU/LV in patients with advanced pancreatic cancer after gemcitabine failure.Methods: We conducted a single institution, retrospective analysis of response, survival and safety in patients who had been treated with nal-IRI with 5-FU/LV. Patients with metastatic pancreatic ductal adenocarcinoma previously treated with gemcitabine-based therapy received nal-IRI (80 mg/m2) with 5-FU/LV every 2 weeks. Kaplan-Meier analysis was performed to obtain median progression free survival and median overall survival. The hazard ratio and 95% confidence interval (CI) were estimated using a stratified Cox regression model. A multivariate Cox proportional hazards regression model was used to identify the effects of clinical factors.Results: Fifty-one patients received nal-IRI plus 5-FU/LV between January 2015 and December 2020. The median age was 67 years, and males were 58.8%. A total of 40 (78.4%) and 11 (21.6%) patients had received one and two lines of prior chemotherapy before enrollment, respectively. Median progression-free survival was 2.8 months (95% CI 1.8-3.7) and median overall survival was 7.0 months (95% CI 6.0-7.9). Chemotherapy doses were reduced or delayed in 33 (64.7%) patients during the first 6 weeks and median relative dose intensity was 0.87. Thirty-six (70.6%) patients experienced grade 3 or 4 adverse events, most commonly neutropenia (58.8%). Most non-haematologic adverse events were under grade 2. Since the start of first-line chemotherapy, median overall survival was 16.3 months (95% CI 14.1-18.4).Conclusions: Nal-IRI plus 5-FU/LV seems to be effective, with manageable toxicities, following gemcitabine-based treatment in patients with metastatic pancreatic ductal adenocarcinoma. Nal-IRI plus 5-FU/LV following gemcitabine with nab-paclitaxel is a feasible sequential treatment option in patients with metastatic pancreatic cancer.Trial Registration: Retrospectively registered. [ABSTRACT FROM AUTHOR]

Approximately 80% of pancreatic cancer is diagnosed at an advanced stage, due to lack of or vague symptoms when the cancer is still localized, leading to a high mortality rate. Known risk factors for developing pancreatic cancer are family history, obesity, type 2 diabetes, and alcohol and tobacco use. There has been a remarkable development in diagnosis modalities and molecular testing, but early detection is still infrequent. The majority of clinical trials have not shown significant efficacy in pancreatic cancer, and treatment strategy remains limited. Additional prognostic factors should be highlighted to obtain appropriate treatment options, including precision medicine, and improve survival outcomes. After the PRODIGE study in 2011 and the MPAC trial in 2013, a new drug (liposomal irinotecan; Onivyde ®) appeared in the strategy, especially after failure of gemcitabine-based treatment. In 2016, the NAPOLI-1 trial showed evidence of the efficacy of the liposomal irinotecan combination (liposomal irinotecan +5-fluorouracile + folinic acid); now, it is considered the standard treatment for relapsing patients. Since NAPOLI-1, real-world data have provided similar results. Herein, we report the story of a 61-year-old woman who was treated with liposomal irinotecan combination (nal-IRI/5-FU/LV) for 8 months with good surgical response, but treatment was discontinued due to economic burden. After the start of treatment (or 1? cycle of liposomal irinotecan treatment), the patient was in a better condition. The liver metastases had disappeared. The combination with liposomal irinotecan was re-administered with patient's approval. Upon rechallenge with the liposomal irinotecan combination, she showed a partial response, and the treatment was given for 7 months. In this report, we tried to identify the prognostic factors leading to the efficacy of the liposomal irinotecan combination. [ABSTRACT FROM AUTHOR]

BackgroundThe NAPOLI-1 trial demonstrated that liposomal irinotecan in combination with fluorouracil (5-FU) and leucovorin (LV) prolonged survival with a manageable safety profile in patients with metastatic pancreatic ductal adenocarcinoma (mPDAC) previously treated with gemcitabine-based therapy. Real-world data on clinical outcomes associated with liposomal irinotecan in NAPOLI-1-based regimens is needed to further substantiate this.MethodsThis real-world, retrospective chart review study included patients with mPDAC who received NAPOLI-1-based regimens from six academic centers in the United States. Liposomal irinotecan initiation defined the index date. Overall survival (OS) and progression-free survival (PFS) were assessed with Kaplan-Meier methodology.ResultsThere were 374 patients evaluated; median age was 68 years, and 51% were female. Among 326 patients with baseline ECOG information, approximately 74% had ECOG score

Background: The NAPOLI-1 trial demonstrated that liposomal irinotecan in combination with fluorouracil (5-FU) and leucovorin (LV) prolonged survival with a manageable safety profile in patients with metastatic pancreatic ductal adenocarcinoma (mPDAC) previously treated with gemcitabine-based therapy. Real-world data on clinical outcomes associated with liposomal irinotecan in NAPOLI-1-based regimens is needed to further substantiate this. Methods: This real-world, retrospective chart review study included patients with mPDAC who received NAPOLI-1-based regimens from six academic centers in the United States. Liposomal irinotecan initiation defined the index date. Overall survival (OS) and progression-free survival (PFS) were assessed with Kaplan-Meier methodology. Results: There were 374 patients evaluated; median age was 68 years, and 51% were female. Among 326 patients with baseline ECOG information, approximately 74% had ECOG score <2. Liposomal irinotecan was administered as a doublet with 5-FU in a NAPOLI-1-based regimen in the first line (1L; 16%), 2L (42%), and 3L+ (42%) of the metastatic setting. For patients treated in 1L, 2L, and 3L+, median [95% confidence interval (CI)] OS was 8.0 [5.1, 11.2], 7.3 [5.3, 8.8], and 4.6 [4.0, 5.7] months, and median [95% CI] PFS was 4.2 [2.2, 6.6], 3.0 [2.6, 3.7], and 2.0 [1.7, 2.2] months, respectively. Conclusions: Patients in a real-world setting treated with NAPOLI-1-based liposomal irinotecan doublet regimens at academic centers were older with poorer performance status compared to trial patients yet had similar outcomes and efficacy. Furthermore, liposomal irinotecan was frequently used in the 3L+ setting where no treatment has been approved and provided clinical benefit. [ABSTRACT FROM AUTHOR]

Background: This multicentre, open‐label study evaluated the efficacy and safety of antiprogrammed death ligand 1 antibody SHR‐1316 plus liposomal irinotecan and 5‐fluorouracil as the first‐line treatment for patients with advanced esophageal squamous cell carcinoma (ESCC). Methods: Eligible patients received SHR‐1316 (10 mg/kg), liposomal irinotecan (60 mg/m2 for the first cycle, 80 mg/m2 thereafter), and 5‐fluorouracil (2400 mg/m2) every 14 days until disease progression, intolerable toxicity or withdrawal of consent. The primary endpoint was progression‐free survival (PFS). Secondary endpoints were objective response rate (ORR), disease control rate (DCR), overall survival (OS), and safety. Results: We enrolled 23 patients between 11 March 2019 and 31 May 2019. The median follow‐up duration was 15.2 months (95% CI 14.2–16.2). The median PFS was 8.5 months (95% CI 1.2–15.8), and ORR and DCR were 52.2% (95% CI 30.1–74.3) and 73.9% (95% CI 54.5–93.3), respectively. The median OS was 11.6 months (95% CI 6.7–16.6). The most common treatment‐related grade 3–4 adverse events (AEs) were neutropenia (17.4%), nausea (13.0%), and anorexia (13.0%). Treatment‐related serious AEs occurred in two patients. No treatment‐related deaths occurred. Conclusions: SHR‐1316 plus liposomal irinotecan and 5‐fluorouracil has a promising efficacy and manageable safety profile, and could be a new first‐line treatment approach for patients with unresectable locally advanced or distant metastatic ESCC. [ABSTRACT FROM AUTHOR]

Introduction: Liposomal irinotecan (nal-IRI) plus fluorouracil/leucovorin (5-FU/LV) has shown clinical benefit in patients with metastatic pancreatic adenocarcinoma (mPAC) who progressed on gemcitabine-based chemotherapy. However, its role in patients with mPAC previously treated with conventional irinotecan-containing chemotherapy has not been appropriately investigated. Methods: In this retrospective analysis, patients with mPAC who received nal-IRI plus 5-FU/LV after conventional irinotecan-containing regimen between January 2017 and March 2020, were identified from two referral cancer centers in South Korea. The ratio of time to progression (TTP) with nal-IRI plus 5-FU/LV to TTP with conventional irinotecan (TTPr) was analyzed with respect to the duration and cumulative dose of conventional irinotecan treatment. Results: In total, 35 patients treated with nal-IRI plus 5-FU/LV after the irinotecan-containing regimen were analyzed. The median age was 58 years and 16 (46%) patients were male. The median duration of conventional irinotecan therapy was 4.6 months at a median cumulative dose of 1230 mg. The objective response rate of nal-IRI plus 5-FU/LV was 2.9%, and stable disease was achieved in 11 (31.4%) patients. During the median follow-up of 9.2 [95% confidence interval (CI): 7.8–10.5] months, the median progression-free survival (PFS) and overall survival (OS) were 2.0 (95% CI: 1.4–2.6) months and 4.4 (95% CI: 3.6–5.7) months, respectively. The 6-month PFS and OS rates were 16.3% and 37.5%, respectively. The median TTPr was 0.41 (range, 0.07–2.07), showing a negative correlation with the cumulative dose of prior irinotecan therapy (R = −0.37, p = 0.041). A tentative negative correlation between TTPr and duration of prior irinotecan therapy was observed (R = −0.35, p = 0.062). The most common grade 3–4 toxicities were neutropenia (20%) and fatigue (8.6%). Conclusion: Nal-IRI plus 5-FU/LV showed modest effectiveness and manageable toxicities for patients with mPAC previously treated with conventional irinotecan-containing chemotherapy. The cumulative dose of prior conventional irinotecan therapy may be inversely correlated with the effectiveness of nal-IRI plus 5-FU/LV. [ABSTRACT FROM AUTHOR]

Aim: This study sought to understand the association between liposomal irinotecan dose reductions (DRs) and clinical outcomes among patients with metastatic pancreatic ductal adenocarcinoma. Materials & methods: A retrospective study of adult patients with metastatic pancreatic ductal adenocarcinoma treated with liposomal irinotecan in the Flatiron Health database was conducted to assess treatment and clinical outcomes. Results: DRs occurred in 28.4% of the 320 patients in the study. Patients with DRs had longer overall survival (7.7 [95% CI: 6.2-10.2]) vs 3.6 [3.2-4.1] months) and time to discontinuation (4.2 [3.0-4.9] vs 1.4 [1.0-1.5] months) than patients without DRs. Results were consistent in a validation analysis requiring three cycles of treatment. Conclusion: Liposomal irinotecan DRs were associated with improved clinical outcomes compared with patients without DRs. [ABSTRACT FROM AUTHOR]

There are questions surrounding the real-world effectiveness of chemotherapeutic treatments for pancreatic ductal adenocarcinoma. This literature review compared the clinical characteristics and outcomes of available real-world evidence (RWE) for liposomal irinotecan in combination with 5-fluorouracil (5-FU) and leucovorin (LV), a treatment regimen indicated for patients with metastatic pancreatic ductal adenocarcinoma (mPDAC) who previously progressed on gemcitabine-based therapy. A targeted literature search was conducted in the PubMed Central® and Embase® databases to identify available RWE regarding patients with mPDAC receiving liposomal irinotecan published within the last 5 years (January 2014–September 2019). Data were extracted for prior lines of therapy, performance status, overall survival (OS), progression-free survival (PFS), duration of exposure, and adverse events. Six studies met inclusion criteria. A comparison of baseline patient characteristics and results with the included evidence reveals a clinically fragile, real-world patient population in terms of age (range: 61–68), prior lines of therapy with 34–61% of patients receiving ⩾2 lines of lines of prior therapy and performance status [49.8–100% of patients with Eastern Cooperative Oncology Group (ECOG) 0–1]. Studies observed wide OS (range: 5.3–9.4 months) and similar PFS (range: 2.3–4.1 months), with two studies measuring duration of exposure (7.3 weeks, 3.1 months). Patients analyzed by RWE studies tended to be older with significant disease progression, poor performance status, and more heavily pretreated compared with the phase III registrational trial (NAPOLI-1). Despite this, patients treated with liposomal irinotecan + 5-FU/LV therapy had similar outcomes as those in NAPOLI-1. [ABSTRACT FROM AUTHOR]

At 9%, and 2% when diagnosed at advanced stage, the 5-year relative survival rate for pancreatic ductal adenocarcinoma (pdac) is the lowest of any cancer. The currently approved treatment options for metastatic pdac in the United States are folfirinox [irinotecan-fluorouracil (5fu)-leucovorin (lv)-oxaliplatin], gemcitabine-nab-paclitaxel, and liposomal irinotecan plus 5fu-lv. Liposomal irinotecan is a novel formulation of irinotecan encapsulated within a lipid bilayer, which favours local metabolic activation. The napoli-1 trial demonstrated the efficacy of liposomal irinotecan in combination with 5fu and lv for the treatment of advanced pdac after progression on gemcitabine-based chemotherapy. The 1-year survival in those patients was 25%; however, none had had irinotecan-refractory disease before treatment with liposomal irinotecan. Furthermore, the U.S. National Comprehensive Cancer Network guidelines recommend liposomal irinotecan plus 5fu-lv in patients who have received prior fluoropyrimidine-based therapy if no prior irinotecan therapy has been given. Here, we report a male patient with stage iv cancer of pancreas or bile duct (site unconfirmed) who experienced a prolonged (51 weeks) response to liposomal irinotecan plus 5fu-lv despite prior disease progression on irinotecan. Several factors have previously been associated with long-term survival in patients receiving liposomal irinotecan therapy: no prior irinotecan-based chemotherapy, high Karnofsky performance status score, age 65 years or less, serum carbohydrate antigen 19-9 less than 59 U/mL, neutrophil-to-lymphocyte ratio 5 or less, and absence of liver metastasis. The patient in the present report had none of those characteristics indicative of long-term survival, except his age at diagnosis--47 years. [ABSTRACT FROM AUTHOR]

The global, randomized NAPOLI‐1 phase 3 trial reported a survival benefit with liposomal irinotecan (nal‐IRI) plus 5‐fluorouracil/leucovorin (nal‐IRI+5‐FU/LV) in patients with metastatic pancreatic ductal adenocarcinoma (mPDAC) after previous gemcitabine‐based therapy. Median overall survival (OS) with nal‐IRI+5‐FU/LV was 6.1 vs 4.2 months with 5‐FU/LV alone (unstratified hazard ratio [HR] = 0.67, P =.012). Herein, we report efficacy and safety results from a post‐hoc subgroup analysis of Asian patients treated at Asian centers. Primary study endpoint was OS; secondary endpoints included progression‐free survival (PFS), objective response rate (ORR), and safety. Patients receiving nal‐IRI+5‐FU/LV (n = 34) had significantly longer median OS versus 5‐FU/LV (n = 35) (8.9 vs 3.7 months; unstratified HR = 0.51, P =.025). Patients had significantly increased median PFS with nal‐IRI+5‐FU/LV versus 5‐FU/LV (4.0 vs 1.4; unstratified HR = 0.48, P =.011), and increased ORR (8.8% vs 0; P =.114). nal‐IRI monotherapy (n = 50) numerically improved efficacy endpoints versus 5‐FU/LV (n = 48): median OS was 5.8 versus 4.3 months (HR = 0.83, P =.423) and median PFS was 2.8 versus 1.4 months (HR = 0.69, P =.155). Grade ≥3 neutropenia was reported more frequently with nal‐IRI+5‐FU/LV versus 5‐FU/LV (54.5% vs 3.4%), and incidence of grade ≥3 diarrhea was comparable between the two arms (3.0% vs 6.9%). This subgroup analysis confirms nal‐IRI+5‐FU/LV as an efficacious treatment option that improves survival in Asian patients with mPDAC that progressed after gemcitabine‐based therapy, with a safety profile agreeing with previous findings. The nal‐IRI+5‐FU/LV regimen should represent a new standard of care for these patients in Asia. (Clinicaltrials.gov: NCT01494506) [ABSTRACT FROM AUTHOR]

Background: Liposomal irinotecan (nal-IRI) plus 5-fluorouracil and leucovorin (5-FU/LV) was effective and well-tolerated in patients with metastatic pancreatic adenocarcinoma (mPAC) that progressed on gemcitabine-based therapy in the global NAPOLI-1 trial. Real-world data may further clarify the outcomes and safety profile of nal-IRI + 5-FU/LV in clinical practice. Methods: This retrospective analysis included patients with mPAC who received nal-IRI + 5-FU/LV following gemcitabine-based therapy under a Managed Access Program in Korea. Results: From January 2017 to April 2018, 86 patients across 10 institutions received nal-IRI + 5-FU/LV (median age, 61 years; 60% male; ECOG performance status, 0–1). A total of 35 (41%) and 51 (59%) patients had received less than two and two or more lines of chemotherapy before inclusion, respectively. At a median follow up of 6.4 months, median overall survival (OS) was 9.4 months (95% confidence interval [CI] 7.4–11.4) and median progression-free survival (PFS) was 3.5 months (95% CI 1.3–5.7). Six-month OS and PFS rates were 65.1% and 37.5%, respectively. Objective response and disease control rates were 10% and 55%, respectively. Most common grade 3–4 toxicities were neutropenia (37.2%), nausea (10.5%), vomiting (9.3%), anorexia (8.1%) and diarrhoea (4.7%). Conclusion: Real-life data for Korean patients indicate that, consistent with NAPOLI-1, nal-IRI + 5-FU/LV is effective and well-tolerated in patients with mPAC that progressed on gemcitabine-based therapy. [ABSTRACT FROM AUTHOR]

Background: Nanoliposomal irinotecan (nal-IRI) plus 5-fluorouracil/leucovorin (5-FU/LV) is a novel treatment option for gemcitabine-pretreated metastatic pancreatic adenocarcinoma (PAC) patients, but real-world evidence is rare. Our aim was to determine the effectiveness and tolerability of this regimen in advanced PAC patients and to compare it with oxaliplatin plus fluoropyrimidines in the second-line setting after failure of gemcitabine. Methods: This is a retrospective single-center analysis of all patients who have been treated with nal-IRI plus 5-FU/LV. To compare its effectiveness with other second-line treatment options, all patients who had received oxaliplatin plus fluoropyrimidines after gemcitabine-based chemotherapy were also eligible for analysis. Results: Fifty-two patients were treated with nal-IRI plus 5-FU/LV between April 2016 and August 2018. The median progression-free survival (PFS) was 3.84 months and the median overall survival (OS) was 6.79 months. Median OS from the beginning of the treatment for advanced disease was 19.9 months. Median PFS in patients that received nal-IRI plus 5-FU/LV as second-line treatment after gemcitabine-based chemotherapy was 4.49 months whereas median PFS in a matched cohort of patients treated with oxaliplatin plus fluoropyrimidines was 3.44 months (p = 0.007). Between these two groups the median OS of patients with CA 19-9 levels above the statistical median (⩾772.8 kU/l) differed significantly (9.33 versus 6.18 months, p = 0.038). Conclusion: Our data confirms the effectiveness of nal-IRI plus 5-FU/LV treatment as a well-tolerated regimen in the treatment of advanced PAC and extends available data on its use as a second-line treatment option when compared with oxaliplatin plus fluoropyrimidines. [ABSTRACT FROM AUTHOR]

Pancreatic cancer is a highly lethal disease, where the mortality closely matches increasing incidence. Pancreatic ductal adenocarcinoma (PDAC) is the most common histologic type that tends to metastasize early in tumor progression. For metastatic PDAC, gemcitabine had been the mainstay treatment for the past three decades. The treatment landscape has changed since 2010, and current first-line chemotherapy includes triplet drugs like FOLFIRINOX (folinic acid, 5-fluorouracil, irinotecan, and oxaliplatin), and doublet agents like nab-paclitaxel and gemcitabine. Nanoliposomal encapsulated irinotecan (nal-IRI) was developed as a novel formulation to improve drug delivery, effectiveness, and limit toxicities. Nal-IRI, in combination with leucovorin-modulated fluorouracil (5-FU/LV), was found in a large randomized phase III clinical trial (NAPOLI-1) to significantly improve overall survival in patients who progressed on gemcitabine-based therapy. This review will focus on the value of using nal-IRI, toxicities, recent clinical experiences, and tools to improve patient outcomes in this setting. [ABSTRACT FROM AUTHOR]

Pancreatic ductal adenocarcinoma (PDAC) is a lethal disease. The majority of patients are diagnosed with locally advanced or metastatic disease with a prognosis of short months. Therapeutic options are limited and until recently, there was no standard second-line chemotherapy option. Liposomal constructs have been engineered to encapsulate chemotherapy thereby preventing premature metabolism, improving distribution and minimizing toxicity. Favourable preclinical data on liposomal irinotecan and early phase trials, led to a recently published phase III trial of liposomal irinotecan in combination with fluorouracil and folinic acid in patients with metastatic PDAC, who progressed after gemcitabine-based chemotherapy. As a direct result, the United States Food and Drug Administration (FDA) and European Medicines Agency (EMA) have approved the use of liposomal irinotecan in this setting. However, first-line treatment options for this disease now include the combination regimen, FOLFIRINOX, in patients with good performance status, and the role of second-line combination treatment with liposomal irinotecan in this setting is unclear. Recent advances have changed the therapeutic landscape, as clinicians are now able to choose a sequential approach to treatment tailored to the individual patient characteristics. This article reviews current treatment options for metastatic PDAC and focuses on the efficacy, safety and place in therapy of liposomal irinotecan. [ABSTRACT FROM AUTHOR]

Background Multiple preclinical studies have shown cytotoxic synergy involving combinations of poly (ADP-ribose) polymerase (PARP) inhibitors and topoisomerase 1 (TOP1) inhibitors, but such combinations have proven too toxic in clinical trials. Liposomal irinotecan (nal-IRI) achieved similar intratumoral exposure with better antitumor activity than the conventional TOP1 inhibitor irinotecan in preclinical models. Tumor targeted delivery of TOP1 inhibitor using nal-IRI and an intermittent schedule of administration of PARP inhibitor may provide a tolerable combination. Methods A phase I study was performed to evaluate the safety and tolerability of escalating doses of nal-IRI and the PARP inhibitor veliparib in patients with solid tumors resistant to standard treatments. Nal-IRI was administered on days 1 and 15 and veliparib on days 5-12 and 19-25 in 28-day cycles. Results Eighteen patients were enrolled across 3 dose levels. Five patients encountered dose–limiting toxicities, including grade 3 diarrhea lasting more than 72 h in 3 patients and 1 patient each with grade 4 diarrhea and grade 3 hyponatremia. The most common grade 3 or 4 toxicities included diarrhea (50% of patients), nausea (16.6%), anorexia, and vomiting (11.1% each) (Table 1). There was no difference in frequencies of adverse events based on UGT1A1*28 status or prior opioid use (Table 1). Conclusion The clinical trial was terminated due to high frequency of unacceptable gastrointestinal toxicities, which precluded dose escalation of veliparib in combination with nal-IRI (ClinicalTrials.gov Identifier: NCT02631733). [ABSTRACT FROM AUTHOR]