Liposomal Irinotecan Research Articles

A case of pathological complete response with liposomal irinotecan + 5-FU/LV for unresectable locally advanced pancreatic cancer

BackgroundPancreatic 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 presentationA 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.ConclusionsWe 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.

Health-related quality of life (HRQoL) in patients (pts) with progressive, poorly differentiated, extra-pulmonary neuroendocrine carcinoma (PD-EP-NEC) enrolled in NET-02: A phase II trial of liposomal irinotecan (nal-IRI)/5-fluorouracil (5-FU)/folinic acid or docetaxel as second-line therapy.

293 Background: NET-02 was a multi-centre, randomised (1:1), non-comparative phase II trial of nal-IRI/5-FU/folinic acid (ARM A) or docetaxel (ARM B) in pts with progressive PD-EP-NEC, aimed at selecting a treatment for evaluation in a phase III trial. Primary analysis (N = 58) showed ARM A, but not ARM B, achieved the target 6-month progression-free survival rate primary endpoint (McNamara et al. ASCO 2022). HRQoL was a secondary endpoint in NET-02. Methods: HRQoL was assessed using the EORTC QLQ-C30 and GINET21 (at baseline (BL), 6-weekly intervals and at disease progression). The mean change from BL was estimated for each scale by timepoint and treatment arm. Results are presented where there were ≥4 responses per time point. Scores were considered stable if they did not change by > 10 points from BL. The mean BL C30 scores for all pts were compared to United Kingdom (UK) population normative C30 data using a 2-sample t-test. Results: Fifty-four of 58 pts (93%) completed a BL questionnaire; of these, 39 (72%) completed ≥1 post-BL questionnaire, with 21 (51%) completing questionnaires at progression. Global health status (GHS) and all functional scales in ARM A remained stable from BL to intervals pre-progression, with a sustained improvement in role functioning observed post-BL. In ARM B, GHS and all C30 functional scales decreased by > 10 points between BL and week 18 (worsening of QoL). Both arms had a > 10-point increase from BL in constipation and diarrhoea in ≥1 post-BL time point. In ARM A, pain, insomnia and financial problems decreased from BL. No C30 symptom scales in ARM B were consistently lower post-BL. Patterns of change in GINET21 mean score were similar in both arms: body image, disease-related worries, information/communication, sexual function and social function all had a > 10-point reduction in score from BL (indicating improvement in symptoms/problems); endocrine and gastrointestinal symptoms remained stable; muscle/bone pain varied across time points, initially showing a reduction in pain followed by an increase, compared to BL. In comparison to the UK C30 norms (BL all pts), 11 of 15 C30 scales did not significantly differ (P > 0.05). Mean scores for fatigue and appetite loss were significantly higher than UK C30 norms (worse symptoms in pts from NET-02) (P = 0.03, P = 0.0003 respectively). However, emotional functioning and GHS were significantly better in pts from NET-02 (P = 0.001, P = 0.03 respectively). Role and social functioning were lower in pts from NET-02 (both P = 0.06) (poorer level of functioning). Conclusions: HRQoL was maintained and potentially improved with nal-IRI/5-FU/folinic acid, but not docetaxel. Compared to the UK general population, BL QoL did not substantially differ in pts from NET-02. Clinical trial information: NCT03837977.

LBA61 HR070803 plus 5-FU/LV versus placebo plus 5-FU/LV in second-line therapy for gemcitabine-refractory locally advanced or metastatic pancreatic cancer: A multicentered, randomized, double-blind, parallel-controlled phase III trial (HR-IRI-APC)

Irinotecan liposome plus 5-FU/LV is one of the standard therapy for metastatic pancreatic cancer(mPC) with failed to gemcitabine-based therapy. HR070803 is a liposome formulation of irinotecan and this study aimed to investigate the efficacy and safety of HR070803 plus 5-FU/LV versus placebo plus 5-FU/LV as the second-line treatment in patients with locally advanced pancreatic cancer(LAPC) or mPC who failed to gemcitabine-based therapy.

55P Final results from the NIFTY trial, a phase IIb, randomized, open-label study of liposomal Irinotecan (nal-IRI) plus fluorouracil (5-FU)/leucovorin (LV) in patients (pts) with previously treated metastatic biliary tract cancer (BTC)

The NIFTY trial showed that nal-IRI plus 5-FU/LV significantly improved the blinded-independent central review (BICR)- and investigator-assessed progression-free survival (PFS) and overall survival (OS) compared with 5-FU/LV. An updated analysis (data cutoff: 31 DEC 2021) was performed to assess the long-term efficacy outcomes (extension follow-up of 1.3 years). As there was a concern about the large discrepancy rates (30%) between BICR and investigator review in the previous analysis, BICR was performed again by three independent radiologists with more experience in clinical trials and also through external monitoring.

53MO Nal-IRI and 5-FU/LV compared to 5-FU/LV in patients with cholangio- and gallbladder carcinoma previously treated with gemcitabine-based therapies (NALIRICC – AIO-HEP-0116)

Therapeutic options in pre-treated advanced biliary tract cancer (BTC) are limited. Although the ABC-06 trial demonstrated clinical benefit for mFOLFOX, there is an unmet need for more effective 2nd line therapies. The aim of this study was to evaluate the efficacy of pegylated liposomal irinotecan formulation (nal-IRI)/5-FU/leucovorin (LV) compared to 5-FU/LV in 2nd line BTC. NALIRICC is a prospective, randomized, two-sided, phase II study. Pts > 18 years, with ECOG PS 0/1, histologically confirmed metastatic BTC and progression on 1st line Gemcitabine-based therapy were eligible. Trial interventions were Arm A nal-IRI (80 mg/m2) plus 5-FU (2400 mg/m2)/LV (400 mg/m2), q2w or Arm B 5-FU/LV, q2w. Pts were stratified according to primary tumor site, and response was evaluated per RECIST v1.1, every 6 weeks. Primary endpoint (EP) was progression-free survival (PFS). Secondary EPs were overall survival (OS), overall response rates (ORR), safety and QoL (EORTC QLQ C30). This study was designed to improve median PFS from 1.5 months (P0) to 3 months (P1; HR 0.5) with 2-sided α of 0.05, power of 90.3%; 99 pts required in total. In total 100 pts were randomized in 17 German centers (49 pts: nal-IRI/5-FU/LV arm/ 51 pts: 5-FU/LV arm). 64/19/17 pts had intra-/extrahepatic/gallbladder cancers. Pt characteristics were well balanced between the two arms. Trial results see the table. Most common grade ≥3 Adverse Events in nal-IRI/5-FU/LV group were decreased neutrophil counts (16.6%), diarrhea (14.6%), and nausea (8.3%). 27.5% of patients in the 5-FU/LV groups received irinotecan-based therapies post-progression. QoL was similar between both arms.Table: 53MONALIRICC-Trial results, median follow-up of 5,9 monthsTreament armORR [%]mOS [months]mPFS [months]AEs ≥ 3 in % of ptsArm A, Nal-IRI and 5-FU/LV, n=4914.36.92.7670.8Arm B, 5-FU/LV, n=513.98.212.350 Open table in a new tab The NALIRICC-trial did not meet its primary EP. The addition of nal-IRI to 5-FU/LV did not improve PFS or OS compared to 5-FU/LV alone and was associated with higher toxicity. 5FU/LV may be considered as a reasonable alternative in 2nd line advanced BTC.

The Efficacy of Liposomal Irinotecan Plus Fluorouracil/Leucovorin as First-Line Therapy in Patients With Locally Advanced or Metastatic Pancreatic Ductal Adenocarcinoma

Chiang, Cho-Han MD, MMSc; Chiang, Cho-Hung MD; Chiang, Cho-Hsien MD; Chiu, Jing-Huey BS; Ma, Kevin Sheng-Kai DDS; Chen, Brian Shiian BS; Luan, Yu-Ze BS; Cheng, Teng-Chieh BS; Hsieh, Ching-Lung MD; Peng, Cheng-Ming MD, PhD Author Information

Dosing Pattern and Early Cumulative Dose of Liposomal Irinotecan in Metastatic Pancreatic Cancer: A Real-World Multicenter Study.

IntroductionThis multicenter, real-world cohort study aimed to evaluate the effectiveness of early cumulative dose administration and dosing pattern of liposomal irinotecan plus fluorouracil/leucovorin (nal-IRI+5-FU/LV) in patients with gemcitabine-refractory metastatic pancreatic ductal adenocarcinoma (mPDAC).Material and MethodsThe electronic medical records of mPDAC patients treated with nal-IRI+5-FU/LV in nine participating centers were manually reviewed. To accommodate to the NAPOLI-1 study population, only patients with an Eastern Cooperative Oncology Group Performance Score of 0–1 were included. The survival impact of the relative 6-week cumulative dose and dosing pattern (standard vs. reduced starting dose, with and without further dose modification) were investigated.ResultsOf the 473 included patients, their median overall survival (mOS) was 6.8 [95% CI, 6.2–7.7] months. The mOS of patients who received a relative 6-week cumulative dose of >80%, 60%–80%, and <60% were 7.9, 8.2, and 4.3 months, respectively (p<0.0001). Their survival impact remained significant after covariate adjustment using Cox regression. The mOS was 8.0–8.2 months in patients with a standard starting dose with and without early dose modification, and 9.3 and 6.7 months in those who had a reduced starting dose with and without escalation in the subsequent treatment, respectively. The incidence of grade 3–4 neutropenia and diarrhea was 23.3% and 2.7%, respectively.ConclusionOur results support the use of nal-IRI+5-FU/LV in gemcitabine-refractory mPDAC and suggest that a lower starting dose followed by a re-escalation strategy could achieve clinical outcomes comparable to those with standard starting doses in real-world practice.

Abstract 3255: Probing and overcoming KRASG12C inhibitor resistance by combination with a pan-KRAS SOS1 inhibitor

Abstract The recent accelerated approval of the KRASG12C mutant-selective inhibitor sotorasib (AMG 510) for the treatment of 2nd line KRASG12C mutation-positive NSCLC patients marks the first approved targeted therapy for tumors with any KRAS mutation. While KRASG12C inhibitors deliver clinical benefit, most patients who achieved an objective response ultimately progressed. Recent insights into clinical KRASG12C inhibitor resistance identified reactivation of the RAS/MAPK pathway as a common putative driver mechanism of resistance. Multiple ongoing trials seek to augment responses to KRASG12C inhibitors through rational combination strategies, including the pan-KRAS SOS1 inhibitor BI 1701963. Here we use different preclinical experimental approaches to interrogate KRASG12C inhibitor resistance mechanisms with the aim to identify strategies to overcome resistance. To predict on-target resistance, Ba/F3 cells were transduced with KRASG12C, ENU-mutagenized and chronically exposed to KRASG12C inhibitors. Resistant clones were screened for secondary KRAS mutations, highlighting that KRAS G12C/Y96D and Y96S cis mutations did confer resistance to KRASG12C inhibition but could be overcome by MEK inhibitor combination with a SOS1 inhibitor. As second strategy a high-complexity single site variant library of KRASG12C encompassing all possible secondary KRAS mutations was employed to establish Ba/F3 transgenic cell pools. The response of this KRASG12C Ba/F3 clone library harboring a comprehensive set of secondary mutations was tested following treatment with KRASG12C inhibitors alone and in combination with a pan-KRAS SOS1 inhibitor. In parallel, acquired KRASG12C inhibitor resistance was generated in solid cancer cells following long-term MRTX849 treatment. Clones were characterized and their response to KRASG12C inhibition and combination therapy was analyzed. Both in the Ba/F3 cell pool as well as in KRASG12C inhibitor resistant clones combining SOS1 inhibition to KRASG12C inhibition proved to be beneficial. Finally, bringing these findings in vivo, SW837(CRC) tumor-bearing mice were long-term treated with adagrasib until tumors relapsed after initial regression and resistant tumors were randomized for second line treatments. In this KRASG12C inhibitor resistant context, treatment with adagrasib plus cetuximab resulted in tumor stasis and adagrasib plus SOS1i resulted in tumor regression. While more work is currently being undertaken to map the resistance mechanisms in both our in vitro and in vivo settings, all results highlight the benefit of combining a SOS1 inhibitor with a KRASG12C inhibitor to prevent and/or overcome acquired resistance. The pan-KRAS SOS1 inhibitor BI 1701963 is the first direct RAS signaling modifier in phase I clinical trials both as a monotherapy as well as in combination with KRASG12C inhibitors, MEK inhibitors and liposomal irinotecan. Citation Format: Marco H. Hofmann, Sabine Jurado, Daniel Gerlach, Takamasa Koga, Francesca Trapani, Michael Gmachl, Donat Alpar, Simone Lieb, Astrid Jeschko, Tetsuya Mitsudomi, Norbert Kraut, Mark P. Petronczki. Probing and overcoming KRASG12C inhibitor resistance by combination with a pan-KRAS SOS1 inhibitor [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 3255.

Abstract 293: Identification of a predictive biomarker for liposomal nanoparticle delivery through pan-cancer pooled screening

Abstract Background: Nanoparticles are a modular technology with great promise for cancer treatment, but one obstacle for clinical implementation is a lack of predictive biomarkers to identify patient groups most likely to benefit from specific nanoformulations. We developed a massively parallel pooled screen to investigate genomic factors underlying NP-cancer cell engagement, and report here the identification of a predictive biomarker that is both formulation-specific and cancer lineage agnostic. Methods: We interrogated the interactions of 35 fluorescent nanoparticle formulations (15 liposomal and 25 polymeric) against 488 pooled, barcoded cancer cell lines using fluorescence-activated cell sorting and binned cells based on strength of association. After sequencing, the relative barcode abundance in each bin was used to generate an association score for each nanoparticle-cell line pair. We identified features predictive of NP-cancer cell association by interfacing this score with multi-omic data from the Cancer Cell Line Encyclopedia. Results: Using machine learning model predictions, we identified thousands of candidate biomarkers both across and within formulations. Expression of the lysosomal transporter SLC46A3 was the top ranked random forest feature for all liposome formulations and was prioritized for further study. Univariate analyses confirmed the significance of this candidate biomarker and indicated a negative relationship, such that low expression of SLC46A3 is highly correlated with high nanoparticle association. This inverse relationship held true across all 22 cancer lineages screened and was recapitulated in a non-pooled screen of 13 cancer cell lines with a range of native SLC46A3 expression. To determine whether modulating SLC46A3 expression is sufficient to negatively regulate uptake of liposomes, we developed a toolkit of engineered cell lines by knocking out SLC46A3 in high-expressing T47D cells and inducing overexpression in low-expressing LOXIMVI cells. Consistent with our hypothesis, we show that SLC46A3 expression is inversely correlated with uptake of liposomal, but not polymeric, nanoparticles. To evaluate the potential clinical utility of SLC46A3 as a biomarker, we tested in vivo delivery of an FDA-approved nanoparticle analog, the drug-free version of liposomal irinotecan, to LOXIMVI flank tumors via intratumoral injection and intravenous administration. For both administration methods, we show that low tumor expression of SLC46A3 correlates with significantly improved delivery of liposomal nanoparticles. Conclusions: We identified SLC46A3 as a negative regulator of liposomal nanoparticle delivery to cancer cells both in vitro and in vivo. Given that liposomal nanoparticles comprise the majority of FDA approvals for cancer indications, we propose SLC46A3 may be a clinically actionable biomarker for patient stratification. Citation Format: Joelle P. Straehla, Natalie Boehnke, Hannah Safford, Mustafa Kocak, Matthew G. Rees, Melissa Ronan, Danny Rosenberg, Charles H. Adelmann, Raghu R. Chivukula, Jaime H. Cheah, Hojun Li, Jennifer A. Roth, Angela N. Koehler, Paula T. Hammond. Identification of a predictive biomarker for liposomal nanoparticle delivery through pan-cancer pooled screening [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 293.

Nal-IRI/5-FU/LV versus modified FOLFIRINOX and FOLFIRI as second-line chemotherapy for unresectable pancreatic cancer: A single center retrospective study

BackgroundThe 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. MethodsThis 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. ResultsA 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. ConclusionsGiven 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.

Development of Irinotecan Liposome Armed with Dual-Target Anti-Epidermal Growth Factor Receptor and Anti-Fibroblast Activation Protein-Specific Antibody for Pancreatic Cancer Treatment.

Pancreatic cancer is one of the most common causes of death in Taiwan. Previous studies have shown that more than 90% of pancreatic cancer cells presented epidermal growth factor receptor (EGFR) cell marker, and this marker is thought to be important as it is related to activation of cancer cell proliferation, angiogenesis, and cancer progression. Moreover, tumor-associated fibroblasts were involved in tumor proliferation and progression. In this study, we fabricated an anti-EGFR and anti-fibroblast activation protein bispecific antibody-targeted liposomal irinotecan (BS−LipoIRI), which could specifically bind to pancreatic cancer cells and tumor-associated fibroblasts. The drug encapsulation efficiency of BS−LipoIRI was 80.95%, and the drug loading was 8.41%. We proved that both pancreatic cancer cells and fibroblasts could be targeted by BS−LipoIRI, which showed better cellular uptake efficacy compared to LipoIRI. Furthermore, an in vivo mouse tumor test indicated that BS−LipoIRI could inhibit pancreatic cancer growth up to 46.2% compared to phosphate-buffered saline control, suggesting that BS−LipoIRI could be useful in clinical cancer treatment.

A phase II study to evaluate the safety and efficacy of radiotherapy combined with irinotecan liposome followed by camrelizumab and apatinib for advanced solid tumors that failed standard treatments.

2567 Background: Liposomes deliver the drug to tumors based on enhanced permeability and retention (EPR) effects. Radiotherapy further prompts the distribution of liposomal drugs to tumor sites receiving radiotherapy by altering the tumor microenvironment. In addition, radiotherapy might enhance systemic antitumoral responses to immunotherapy. Herein, we aimed to explore safety and efficacy of radiotherapy in combination with irinotecan liposome, immunotherapy, and antiangiogenic therapy in advanced solid tumors patients (pts) that failed standard treatments. Methods: Anopen single-arm, multi-center, phase II study was conducted to enroll solid tumors pts who have failed standard treatments. Eligible pts would receive radiotherapy combined with irinotecan liposome followed by camrelizumab and apatinib. Radiotherapy of 24 Gy/3 fractions/3-10 days was given to the targeted lesions. Irinotecan liposome (80mg/m2 i.v.) was administered once within 48 hours after radiotherapy and followed by camrelizumab (200mg i.v. q3w) and apatinib (250mg po qd) until disease progression or unacceptable toxicity. The primary endpoint was the objective response rate (ORR) of the irradiated lesions evaluated by the investigators as per RECIST V1.1. The secondary endpoints were disease control rate (DCR) and treatment-related adverse event (TRAE). Results: As of Dec 2021, 55 pts were enrolled includin 9 with biliary tract cancer, 8 with pancreatic cancer, 8 with sarcoma, 5 with lung cancer, 2 with liver cancer, 2 with cervical cancer, 2 with gastric cancer, and 22 with other cancer types. 26 (47.3%) pts failed at least 3 lines of therapy before enrollment. The median follow-up was 41 weeks and 42 pts can be evaluated. 15 partial response, 26 stable disease, and 1 progressive disease were achieved. The ORR and DCR of irradiated target lesions were 35.7% and 97.6%, respectively. The ORR and DCR of every cancer type are listed in table. TRAEs (all grades) occurred in 87.3% (48/55) pts. The most common grade 3-4 related TRAEs were lymphocyte count decreased (29.1%), white blood cell count decreased (10.9%), and anaemia (10.9%). Conclusions: The combination of radiotherapy, irinotecan liposome, camrelizumab, and apatinib demonstrated promising anti-tumor activity and well tolerance in various advanced solid tumors that failed standard treatments. Clinical trial information: NCT04569916. [Table: see text]

A randomized phase II study of gemcitabine and nab-paclitaxel compared with 5-fluorouracil, leucovorin, and liposomal irinotecan in older patients with treatment-naïve metastatic pancreatic cancer (GIANT): ECOG-ACRIN EA2186—Trials in progress.

TPS4185 Background: Evidence-based data is lacking to guide the care of older adults with newly diagnosed metastatic pancreatic cancer (mPCA). As a result, treatment approach and the selection of chemotherapy regimens are often extrapolated from data from younger patients. Furthermore, vulnerable older adults are often treated with dose adjusted regimens with limited data to support this practice. EA2186 is a phase II randomized controlled trial, and the first prospective study aiming to define the optimal treatment approach of vulnerable older adults with newly diagnosed mPCA. Methods: Patients aged 70 years and over with histologically confirmed pancreatic adenocarcinoma, evidence of metastatic disease, ECOG PS 0-2 and adequate organ function, who are considered vulnerable are eligible for this trial (accrual target 184). This study utilizes a screening geriatric assessment which characterize patients as fit, vulnerable or frail by evaluating functional status, cognition and co-morbidities. Vulnerable patients according to this screening assessment are those with mild abnormalities in functional status, comorbidities and/or cognition, or older than 80 years of age. Those patients will be randomized to receive either modified Gemcitabine/Nab-Paclitaxel or dose-reduced 5-Fluorouracil Leucovorin and Liposomal Irinotecan every 2 weeks. A comprehensive geriatric assessment (GA) and quality of life (QOL) evaluation are completed prior to initiation of therapy for all randomized patients. Follow up will continue until disease progression or withdrawal, with repeated GA and QOL assessments at each disease evaluation. Overall survival is the primary objective, with secondary objectives including progression free survival, and response rate. Enrolled patients will be stratified by age 70-74 vs ≥75, and ECOG PS 0-1 vs 2. Additional endpoints of interest for older adults include: evaluation of risk factors identified through GA, and capturing toxicities of interest for this patient population (i.e. hospitalization, deterioration in PS, and falls). Correlative studies include assessment of pro-inflammatory biomarkers or aging in the blood (IL-6 and CRP) as well as imaging evaluation of sarcopenia and body composition as predictors of treatment tolerance. Clinical trial information: NCT04233866.

P-8 Long-term survival in patients with pancreatic cancer (PAC) treated with liposomal irinotecan in combination with 5-fluorouracil and leucovorin (nal-IRI+5-FU/LV)

PAC is an aggressive disease with 85% of patients being diagnosed at a locally advanced or metastatic (mPAC) stage; the prognosis is poor, as only 10% survive beyond 5 years after diagnosis. Current treatments include the use of gemcitabine (GEM)-based therapies in first line, followed by liposomal irinotecan (nal-IRI+5-FU/LV) after failure. Despite poor survival outcomes, some patients survive >1 year from the start of nal-IRI+5-FU/LV. No clear recommendations exist for the optimal treatment sequence with no precise characteristics or molecular markers to help select a chemotherapy regimen or personalized treatment.

A phase II, open-label, pilot study evaluating the safety and activity of liposomal irinotecan (Nal-IRI) in combination with 5-FU and oxaliplatin (NALIRIFOX) in preoperative treatment of pancreatic adenocarcinoma: NEO-Nal-IRI study.

TPS4196 Background: Neoadjuvant treatment for potentially curable pancreatic cancer (PDAC) is increasing in acceptability, but a standard regimen has yet to be established. Multiple studies have demonstrated feasibility and effectiveness of the FOLFIRINOX (5-fluorouracil, leucovorin, oxaliplatin and irinotecan) regimen in the perioperative setting. However, FOLFIRINOX often requires dose modifications, delays and growth factor support due to excessive toxicity which can complicate care delivery when given pre-op. Liposomal irinotecan injection (Nal-IRI) is FDA approved in combination with 5-FU/LV with a well-tolerated safety profile in relapsed, refractory metastatic PDAC. The current study aims to substitute Nal-IRI for traditional irinotecan in the standard FOLFIRINOX regimen (NALIRIFOX) and to demonstrate safe and effective neoadjuvant delivery. Methods: This phase 2, open-label, multicenter single-arm study focuses on patients (pts) with operable PDAC without metastatic disease. Other key eligibility criteria include age ≥18 years, resectability confirmed by multiD GI tumor board (resectable vs. borderline), adequate cardiac, renal, hepatic function and ECOG performance status of 0 to 1. Pts receive NALIRIFOX regimen as per the table every 2 weeks for four months followed by disease reassessment. Pts who remain surgical candidates will undergo surgical resection within 4 to 8 weeks following last dose of therapy. The primary endpoint is to assess safety and feasibility of regimen in pre-op setting. Secondary endpoints include R0 resection rate, clinical, biochemical and radiological response rate and patient-reported quality of life during treatment as measured by the NCI validated FACT-G scale. Enrollment continues to a maximum of 28 evaluable pts to demonstrate a reduction in historical 30-day post-op complication rate. Clinical trial information: NCT03483038. [Table: see text]

Study protocol of an open-label, single-arm, phase II trial investigating the efficacy and safety of trifluridine/tipiracil combined with irinotecan as a second-line therapy in patients with cholangiocarcinoma (TRITICC).

TPS4176 Background: Biliary tract cancers (BTC) currently account for ̃15% of all primary liver cancers and ̃3% of gastrointestinal malignancies. Gemcitabine/Cisplatin has been the standard of care in the first-line therapy of BTC for a decade. Despite recently some survival benefit has been shown in adding a checkpoint inhibitor, further lines of treatment are only poorly defined. In the ABC-06 phase-3 study, second-line FOLFOX demonstrated a moderate but significant improvement of survival and might be regarded as a standard of care. The combination of liposomal Irinotecan and 5-FU infusion pump also improved survival after first line therapy. Both mentioned second-line regimens are based on limited evidence and questionable generalizability. Thus, there is a high need for novel treatment concepts in patients without targetable genetic alterations. Trifluridine/tipiracil (FTD/TPI) is a orally active, antimetabolite agent comprised of trifluridine, a thymidine-based nucleoside analogue, and tipiracil, a potent thymidine phosphorylase inhibitor. Recent reports provided evidence of an antitumor activity of FTD/TPI plus Irinotecan as well in patients with BTC. Therefore, the TRITICC trial was designed to evaluate the safety and efficacy of FTD/TPI plus irinotecan in patients with BTC refractory to previous Gemcitabine based treatment. Methods: TRITICC (NCT04059562) is an interventional, prospective, open-label, non-randomized, exploratory, multicenter, single-arm phase IIA clinical trial that evaluates the safety and efficacy of FTD/TPI (25 mg/m² body surface area (BSA), BID, orally on days 1-5 followed by a 9-days recovery period from day 6 trough day 14 of each 14-days treatment cycle) plus irinotecan (on day 1 of each cycle at a dose of 180 mg/m2) in adult patients with histologically verified locally advanced or metastatic BTC (including cholangiocarcinoma and gallbladder or ampullary carcinoma) with documented radiological disease progression to first-line gemcitabine based chemotherapy. A total of 28 patients is planned to be enrolled in 6 sites across Germany. Study treatment will be continued until disease progression according to RECIST 1.1 criteria or occurrence of unacceptable toxicity. The effect of FTD/TPI plus irinotecan on progression-free survival will be analyzed as primary endpoint. Safety (according to NCI-CTCAE), response rates and overall survival are secondary endpoints. In addition, a comprehensive translational research program is part of the study and might provide findings about predictive markers with regard to response, survival periods and resistance to treatment. Currently, 3 out of the planned 6 German study sites are opened for recruitment and 6 patients have been enrolled. The primary study endpoint is estimated to be evaluated in 2023. Clinical trial information: NCT04059562.

NET-02: A multicenter, randomized, phase II trial of liposomal irinotecan (nal-IRI) and 5-fluorouracil (5-FU)/folinic acid or docetaxel as second-line therapy in patients (pts) with progressive poorly differentiated extra-pulmonary neuroendocrine carcinoma (PD-EP-NEC).

4005 Background: The prognosis for pts with PD-EP-NEC is poor. A recognised first-line (1L) treatment for advanced disease is etoposide/platinum-based chemotherapy; there is no standard second-line (2L) treatment (area of unmet need). Methods: This was a multi-centre, randomised (1:1), phase II trial of IV nal-IRI (70mg/m2 free base)/5-FU (2400 mg/m2)/folinic acid, Q14 days (ARM A), or IV docetaxel (75mg/m2), Q21 days (ARM B), as 2L therapy in a planned 102 pts with progressive PD-EP-NEC, aimed at selecting a treatment for continuation to a phase III trial. Pts with histologically-confirmed PD-EP-NEC (Ki-67&gt;20%; Grade 3, WHO 2019), who had prior 1L platinum-based chemotherapy and radiological disease progression or discontinuation of 1L therapy due to intolerance, with an ECOG performance status ≤2 were eligible. Randomisation was stratified by Ki-67, ECOG PS, presence of liver metastases, and response to previous platinum-based therapy. Primary endpoint was 6 month (mo) progression-free survival (PFS) rate; 80% power to demonstrate the one-sided 95% confidence interval (CI) of the 6 mo PFS rate excluded 15%, if the true rate was at least 30%, where 30% was the required level of efficacy; a rate of &lt;15% would give grounds for rejection. Intention was to show that the regimens were sufficiently active, but not to assess superiority of one regimen over the other. Secondary endpoints included objective response rate (ORR), PFS, overall survival (OS), and toxicity. Based on futility analysis, the DSMB recommended closure of recruitment in Dec 21. Results: Of 58 patients in 15 UK centres (Nov 18-Dec 21), 29 in ARM A, 29 in ARM B, 57% were male, median age (range): 63.5 years (22-85), 90% ECOG PS 0/1, 10% PS 2, 90% Ki-67≥55%, 33%/38%/29% small/large cell/unknown morphology, primary site: 69% gastrointestinal, 12% unknown, 9% genitourinary, 5% head &amp; neck, 3% gynae, 2% breast, 60% had liver mets, 91%/7%/2% were resistant/sensitive/intolerant to 1L platinum-based treatment. At a median follow up of 6.6 mo, the primary end-point of 6-mo PFS rate was met in ARM A; ORR, median PFS and OS are also presented (Table). Adverse events ≥ grade 3 occurred in 51.7% and 55.2% in ARM A and B and there were 1 and 6 discontinuations due to toxicity in ARM A and B, respectively. Data cleaning is on-going. Conclusions: nal-IRI/5-FU, but not docetaxel, met the primary endpoint (exceeding the threshold for efficacy), with manageable toxicity, and warrants evaluation in a phase III trial. Clinical trial information: 03837977. [Table: see text]

Liposomal irinotecan (Onivyde): Exemplifying the benefits of nanotherapeutic drugs.

Irinotecan is a topoisomerase inhibitor, widely used in treatment of malignancies including pancreatic ductal adenocarcinoma (PDAC) as part of the FOLFIRINOX regimen prescribed as a first‐line treatment in several countries. However, irinotecan has not been successfully introduced as a second‐line treatment for pancreatic cancer and few randomized clinical studies have evaluated its added value. Efficacy of liposomal irinotecan (nal‐IRI) combined with 5‐fluorouracil and leucovorin (5‐FU/LV) was reported in the phase III NAPOLI‐1 trial in metastatic PDAC following failure of gemcitabine‐based therapy. Several features of nal‐IRI pharmacokinetics (PK) could result in better outcomes versus nonliposomal irinotecan. Irinotecan is a prodrug that is converted to active SN‐38 by carboxylesterase enzymes and inactivated by cytochrome P450 3A4/3A5. SN‐38 is inactivated by UGT1A1 enzymes. Individual variations in their expression and activity could influence enhanced localized irinotecan activity and toxicity. Liposomal irinotecan exploits the enhanced permeability and retention effect in cancer, accumulating in tumor tissues. Liposomal irinotecan also has a longer half‐life and higher area under the concentration‐time curve (0–∞) than nonliposomal irinotecan, as the liposomal formulation protects cargo from premature metabolism in the plasma. This results in irinotecan activation in tumor tissue, leading to enhanced cytotoxicity. Importantly, despite the longer exposure, overall toxicity for nal‐IRI is no worse than nonliposomal irinotecan. Liposomal irinotecan exemplifies how liposomal encapsulation of a chemotherapeutic agent can alter its PK properties, improving clinical outcomes for patients. Liposomal irinotecan is currently under investigation in other malignancies including biliary tract cancer (amongst other gastrointestinal cancers), brain tumors, and small‐cell lung cancer.

How to improve metastatic pancreatic ductal adenocarcinoma patients' selection: Between clinical trials and the real-world.

As underlined in the minireview by Blomstrand et al, given the poor prognosis and the paucity of data on a therapeutic sequence in pancreatic ductal adenocarcinoma (PDAC), additional randomized controlled trials and real-world evidence studies addressing current and novel regimens are needed. The real-world outcomes of first-line chemotherapy regimens such as FOLFIRINOX and gemcitabine/nab-paclitaxel are thoroughly reviewed and seem to be largely generalizable in a real-world context. Regarding second-line chemotherapy, the key question about the optimal sequence of regimens remains uncertain. Precisely in this setting, it is therefore useful to encourage the implementation of clinical studies that may contribute to the scarcity of data available up to now. We report our experience with a small group of patients treated with second-line liposomal irinotecan (nal-IRI) plus 5-fluorouracil and leucovorin. To improve the treatment of patients affected by PDAC, it is useful to identify subgroups of patients who may benefit from target treatments (e.g., BRCA mutant) and it is also important to focus on any prognostic factors that may affect the survival and treatment of these patients.

Augmenting Experimental Gastric Cancer Activity of Irinotecan through Liposomal Formulation and Antiangiogenic Combination Therapy.

Gastric adenocarcinoma (GAC) is the third most common cause of cancer-related deaths worldwide. Combination chemotherapy remains the standard treatment for advanced GAC. Liposomal irinotecan (nal-IRI) has improved pharmacokinetics (PK) and drug biodistribution compared with irinotecan (IRI, CPT-11). Angiogenesis plays a crucial role in the progression and metastasis of GAC. We evaluated the antitumor efficacy of nal-IRI in combination with novel antiangiogenic agents in GAC mouse models. Animal survival studies were performed in peritoneal dissemination xenografts. Tumor growth and PK studies were performed in subcutaneous xenografts. Compared with controls, extension in animal survival by nal-IRI and IRI was >156% and >94%, respectively. The addition of nintedanib or DC101 extended nal-IRI response by 13% and 15%, and IRI response by 37% and 31% (MKN-45 xenografts); nal-IRI response by 11% and 3%, and IRI response by 16% and 40% (KATO-III xenografts). Retardation of tumor growth was greater with nal-IRI (92%) than IRI (71%). Nintedanib and DC101 addition tend to augment nal-IRI or IRI response in this model. The addition of antiangiogenic agents enhanced tumor cell proliferation inhibition effects of nal-IRI or IRI. The tumor vasculature was decreased by nintedanib (65%) and DC101 (58%), while nal-IRI and IRI alone showed no effect. PK characterization in GAC xenografts demonstrated that compared with IRI, nal-IRI treatment groups had higher retention, circulation time, and tumor levels of CPT-11 and its active metabolite SN-38. These findings indicate that nal-IRI, alone and in combination with antiangiogenic agents, has the potential for improving clinical GAC therapy.