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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.

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.

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

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.

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.

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.

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.

IntroductionCombination 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.MethodsRadiotherapy 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).ResultsBetween 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%).ConclusionThe combination of radiotherapy, liposomal irinotecan, camrelizumab, and anti-angiogenesis therapy demonstrated promising anti-tumor activity and well tolerance in various advanced solid tumors.Clinical trial registrationhttps://clinicaltrials.gov/ct2/home, identifier NCT04569916.

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 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 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.

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