Search

Nanoliposomal irinotecan (nal-IRI) is a liposomal formulation of irinotecan with a longer half-life (t1/2 ), higher plasma total irinotecan (tIRI), and lower SN-38 maximum concentration (Cmax ) compared with nonliposomal irinotecan. Population pharmacokinetic (PK) analysis of nal-IRI was performed for tIRI and total SN-38 (tSN38) using patient samples from six studies. PK-safety association was evaluated for neutropenia and diarrhea in 353 patients. PK-efficacy association was evaluated from a phase III study in pancreatic cancer NAPOLI1. Efficacy was associated with longer duration of unencapsulated SN-38 (uSN38) above a threshold and higher Cavg of tIRI, tSN38, and uSN38. Neutropenia was associated with uSN38 Cmax and diarrhea with tIRI Cmax . Baseline predictive factors were race, body surface area, and bilirubin. Analysis identified PK factors associated with efficacy, safety, and predictive baseline factors. The results support the benefit of nal-IRI dose of 70 mg/m2 (free-base; equivalent to 80 mg/m2 salt base) Q2W over 100 mg/m2 Q3W.

TPS4664 Background: Pancreatic ductal adenocarcinoma (PDAC) is the deadliest form of cancer with a 5-year survival of less than 5% for patients with metastatic disease. Despite improvements over the past years, with the introduction of FOLFIRINOX and gemcitabine plus nab-paclitaxel, the majority has disease progression within 6 months after start of first line treatment. The NAPOLI trial was the first phase III study showing that patients with metastatic pancreatic cancer that progressed after treatment with gemcitabine-based chemotherapy benefitted from second line treatment. Patients received liposomal irinotecan (nal-IRI) either as a single agent or in combination with 5-fluorouracil/leucovorin (5-FU/LV), or 5-FU/LV alone. Patients treated with both nal-IRI and 5-FU/LV experienced a median overall survival (mOS) of 6.1 months versus 4.2 months for the 5-FU/LV group. Recently, two Japanese studies (GEST and JASPAC 01) reported on the use of S-1 in patients with PDAC. In patients with locally advanced or metastatic PDAC, S-1 was non-inferior compared to gemcitabine in terms of mOS (8.8 months for gemcitabine versus 9.7 months for S-1). In the adjuvant setting, S-1 showed superior mOS compared to gemcitabine, 46.5 and 25.5 months respectively, HR for mortality of S-1 compared with gemcitabine was 0.57 (95% CI 0.44–0.72). In view of these results, the objective of this NAPAN study is to compare the progression free survival (PFS) of nal-IRI plus S-1, with nal-IRI plus 5-FU/LV in a Western study population for second line treatment of PDAC. Methods: This is a multi-center, open label, randomized phase II trial. Patients ≥ 18 years of age with histologically or cytologically confirmed PDAC, previously treated with gemcitabine (-based) therapy, or progression within 6 months of adjuvant gemcitabine-based treatment are eligible. After a safety run-in of the nal-IRI plus S-1 regimen, patients will be randomized between nal-IRI plus S-1 and nal-IRI plus 5-FU/LV. Primary endpoint of the run-in phase is to determine dose limiting toxicity (DLT) and maximum tolerated dose (MTD) of nal-IRI when co-administered with fixed dose S-1. The primary endpoint of the phase II part is to determine the efficacy of the treatment arms in terms of PFS. Secondary endpoints include OS, response rate according to RECIST 1.1, adverse events according to CTC version 5.0 and Quality of life. Until now 2 of the planned 120 patients have been enrolled. Clinical trial information: NCT03986294 .

Gallbladder cancer is associated with a dismal prognosis, and accurate in vivo models will be elemental to improve our understanding of this deadly disease and develop better treatment options. We have generated a transplantation-based murine model for gallbladder cancer that histologically mimics the human disease, including the development of distant metastasis. Murine gallbladder&ndash, derived organoids are genetically modified by either retroviral transduction or transfection with CRISPR/Cas9 encoding plasmids, thereby allowing the rapid generation of complex cancer genotypes. We characterize the model in the presence of two of the most frequent oncogenic drivers&mdash, Kras and ERBB2&mdash, and provide evidence that the tumor histology is highly dependent on the driver oncogene. Further, we demonstrate the utility of the model for the preclinical assessment of novel therapeutic approaches by showing that liposomal Irinotecan (Nal-IRI) is retained in tumor cells and significantly prolongs the survival of gallbladder cancer&ndash, bearing mice compared to conventional irinotecan.

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.

Irinotecan liposomal; Pacients grans; Càncer de pàncrees Irinotecán liposomal; Pacientes mayores; Cáncer de páncreas Liposomal irinotecan; Older patients; Pancreatic cancer Objectives Pancreatic cancer is a highly lethal disease predominantly affecting older patients. Characterization of outcomes in these patients may help optimise treatment decisions. The global, phase 3 NAPOLI-1 trial ( NCT01494506 ) demonstrated an overall survival (OS) benefit with liposomal irinotecan and 5-flurouracil/leucovorin (nal-IRI + 5-FU/LV) versus 5-FU/LV. This subgroup analysis explored impact of age on outcomes in NAPOLI-1 patients, and nal-IRI + 5-FU/LV efficacy and safety in older patients. Materials and Methods This exploratory, post-hoc analysis of the NAPOLI-1 trial included patients aged ≥eighteen years (no upper limit) with metastatic pancreatic adenocarcinoma that had progressed on gemcitabine-based therapy. Patients were stratified by age (cut-offs at 65, 70, and 75 years); OS and progression-free survival (PFS) were estimated by Kaplan-Meier analysis. Results Of 417 randomized patients, 192 (46%), 110 (26%) and 43 (10%) were aged ≥65, ≥70 and ≥ 75 years, respectively. Mortality risk and risk of disease progression were similar in older and younger patients independent of treatment (HRs for median [m]OS/mPFS comparisons were 0.88/0.95 [ .25). Reduced mortality/morbidity risk with nal-IRI + 5-FU/LV in older subgroups was in line with the wider population. No additional toxicities with nal-IRI + 5-FU/LV were observed in older patients: 86% of patients ≥75 years versus 69%

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.

Colorectal cancer (CRC) is the most frequently diagnosed cancer and leading cause of cancer-related deaths worldwide. Because of the use of first-line CRC treatments, such as irinotecan (IRI), is hindered by dose-limiting side effects, improved drug delivery systems may have major clinical benefits for CRC treatment. In this study, we generate and characterize liposomal irinotecan (Lipo-IRI), a lipid-based nanoparticle, which shows excellent bioavailability and pharmacokinetics. Additionally, this formulation allows IRI to be maintained in active form and prolongs its half-life in circulation compared to IRI in solution. Compared with IRI statistically, the level of prostaglandin E2 (PGE2) in colonic tissue decreases, and Bifidobacterium spp. (beneficial intestinal microbiota) content increases in the Lipo-IRI-treated group. Moreover, no damage is observed by the hematoxylin and eosin staining of the normal tissue samples from the Lipo-IRI-treated group. In a xenograft mouse model, CRC tumors shrink markedly following Lipo-IRI treatment, and mice receiving a targeted combination of Lipo-IRI and liposomal doxorubicin (Lipo-Dox) extend their survival rate significantly. Overall, our results demonstrate that this formulation of Lipo-IRI shows a great potential for the treatment of colorectal cancer.

4006 Background: There is no globally established second-line therapy after progression on GemCis in BTC. Although ABC-06 trial showed the clinical benefit of mFOLFOX compared to active symptom control, further investigation is needed. Methods: NIFTY is an investigator-initiated, multicenter, open-label, randomized, phase 2b study. Pts with > 19 years, ECOG PS 0/1, histologically confirmed metastatic BTC, and disease progression on first-line GemCis were eligible. Pts were randomized 1:1 to nal-IRI (70 mg/m2, 90 min) plus 5-FU (2400 mg/m2, 46 hours)/LV (400 mg/m2, 30 min), every 2 weeks or 5-FU/LV, every 2 weeks until disease progression per investigator review or intolerable toxicities (stratification: primary tumor site, prior surgery and institution). Tumor response was evaluated per RECIST v1.1, every 6 weeks (fixed schedule). Primary endpoint is progression-free survival (PFS) per blinded independent central review (BICR). Secondary endpoints were PFS per investigator review, overall survival (OS) overall response rates (ORR), and safety. This study was designed to improve median PFS from 2 months (P0) to 3.3 months (P1; HR 0.6) with 2-sided alpha of 0.05, power of 80% and follow-up loss rates of 10%; a total of 174 pts were required. Results: A total of 178 patients were enrolled between SEP 2018 and FEB 2020; with exclusion of 4 pts who did not receive any study treatment, 174 pts (88 for nal-IRI plus 5-FU/LV group and 86 for 5-FU/LV group) were included in the Full Analysis Set. Median age was 64 yrs (range 37-84); 99/75 pts were male/female; 74/47/53 pts had intrahepatic/extrahepatic/gallbladder cancers. Pts characteristics were well balanced between two arms. With median follow-up duration of 6.1 mo (IQR 3.5-11.2), median PFS per BICR in nal-IRI plus 5-FU/LV group and 5-FU/LV group was 7.1 mo (95% CI, 3.6-8.8) and 1.4 mo (1.2-1.5), respectively (HR=0.56 [0.39-0.81], p=0.0019); median PFS per investigator review was 3.9 mo (2.7-5.2) and 1.6 mo (1.3-2.2), respectively (HR=0.48 [0.34-0.69], p

6025 Background: Liposomal irinotecan (nal-IRI) + 5-FU/LV has been approved and used in treating patients with metastatic pancreatic cancer after gemcitabine-based therapy through the NAPOLI-1 study result. This phase 2 trial evaluated the activity of NAPOLI-1 regimen in patients with squamous cell carcinoma (SCC) of head and neck (H&N) or esophagus that progressed on or recur after platinum-based chemotherapy or concurrent chemoradiotherapy. Methods: Patients with histologically confirmed SCC of H&N or esophagus whose disease progressed while on or progressed/recurred within 6 months after platinum-based chemotherapy or chemoradiotherapy, and unsuitable for further surgical or radiation intervention were eligible. Prior anti-EGFR or anti-PD1/anti-PDL1 treatment was allowed. The regimen consisted of nal-IRI 70 mg/m2 (irinotecan free base) followed by LV 400 mg/m2 and 5-FU 2400 mg/m2, every 2 weeks. A Simon’s 2-stage design was used with planned 30 evaluable patients in the first stage and 52 evaluable patients in total. The primary endpoint is objective tumor response. Results: From December 2018 to April 2020, 59 subjects were enrolled, including 16 with esophagus cancer and 43 with H&N cancer. Thirty-seven (63%) patients had metastatic disease at enrollment. The mean of treatment cycles were 5 (range, 1-21). Among the total 59 enrolled subjects, 53 subjects (14 esophagus cancer, 39 H&N cancer) were evaluable for objective tumor response. The disease control rate in esophagus cancer was 50% (7 SD, intent-to-treat (ITT) population 43.8%). For H&N patients, 1 CR, 4 PR, and 23 SD resulted in the response rate 12.8% (11.6% in ITT population) and disease control rate 72% (65% in ITT population). The median progression free survival (N = 59) was 2.5 months (esophagus/H&N: 1.5/2.7 months) and the median overall survival was 5.9 months (esophagus/H&N: 4.2/7.3 months). Seventy-eight percent of patients had ≥grade 3 treatment-related adverse events. The most frequent ≥grade 3 toxicities were decreased lymphocyte count (50.8%), decreased neutrophil count (42.4%), and decreased white blood count (33.9%). Only 3 patients (5%) had grade 3 diarrhea during the treatment period. Conclusions: This study showed the modest efficacy and manageable toxicity profile of nal-IRI+5-FU/LV in platinum-refractory locally advanced or metastatic H&N or esophagus cancer patients. Clinical benefits including complete tumor response were noted in H&N patients. The role of this regimen in selective patients and the efficacy of combination with immunotherapeutic agents warrant further explorations. Clinical trial information: NCT03712397.

e24027 Background: The ongoing two-part phase 2/3 RESILIENT study (NCT03088813) is investigating the efficacy and safety of liposomal irinotecan monotherapy in patients with SCLC who have progressed on or after first line platinum-based chemotherapy. This exploratory analysis from RESILIENT part 1 was conducted to confirm the psychometric properties of established PRO instruments that had not previously been validated in patients with SCLC. Methods: Patients completed the European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire (EORTC QLQ) Core 30 (C30) and the EORTC QLQ Lung Cancer 13 (LC13) before treatment assignment (baseline), every 6 weeks thereafter, at treatment discontinuation and at the 30-day follow-up visit. Psychometric methods included descriptive statistics (items and scales), correlations (item-to-item and item-to-total), internal consistency (Cronbach’s α), test-retest reliability (intraclass correlation coefficient [ICC], two-way random effects model), construct validity and sensitivity to change. The analysis included patients who received at least one dose of study drug and completed at least one PRO assessment. Results: Thirty patients were enrolled in RESILIENT part 1 and included in the analysis. At baseline, 68% of patients reported ‘not severe’ or ‘mild’ symptoms. Floor effects (i.e. more than 25% of responses of ‘not at all’) were observed for several of the functioning/impact and symptom scales of the EORTC QLQ C30 and LC13. Moderate to strong correlations were found among most questionnaire items within their respective scales. Acceptable evidence for internal consistency and good test-retest reliability were observed. Selected results for the EORTC QLQ LC13, including dyspnea scales, are shown in the Table. The magnitude of correlations among PRO instruments supported evidence for convergent validity in this sample. Conclusions: In RESILIENT part 1, patients experienced low and tolerable symptoms at enrollment, limiting the potential for further improvement. Overall, these PRO instruments had acceptable psychometric properties (e.g. construct validity, reliability and ability to detect change) in this sample. However, these analyses should be repeated in a larger sample using data from RESILIENT part 2. Clinical trial information: NCT03088813. [Table: see text]

Purpose This phase I trial was performed to determine the maximum-tolerated dose (MTD), dose-limiting toxicities (DLTs), preliminary efficacy, and pharmacokinetics (PK) of LY01610, a novel liposome-encapsulated irinotecan, in patients with advanced esophageal squamous cell carcinoma (ESCC). Methods This trial was conducted in two stages. In the dose-escalation stage, patients with advanced ESCC refractory or intolerant to previous chemotherapy received escalating doses of LY01610. A recommended dose based on patient tolerance was then expanded in the second stage. LY01610 was administered intravenously every 2 weeks, except that the first cycle in dose escalation was 3 weeks to allow observation of DLTs. Results Twenty-four patients were enrolled across 4 dose levels (30, 60, 90 and 120 mg/m2). The DLTs included vomiting and febrile neutropenia, and the MTD was 90 mg/m2. The most common grade 3/4 adverse events were leukopenia in six patients (25.0%), anemia in six patients (25.0%) and neutropenia in five patients (20.8%). One patient achieved complete response, and four had partial response, including one patient receiving LY01610 at the starting dose of 30 mg/m2. Compared with conventional irinotecan, the PK profile of LY01610 was characterized by increased and prolonged exposure of total irinotecan and the active metabolite SN-38 in plasma. Conclusion LY01610 demonstrated manageable toxicity and promising anti-tumor activity in patients with advanced ESCC. Future clinical development of LY01610 as single agent or in combination with other anti-cancer agents in treating ESCC patients is warranted. Trial registration NCT04088604 at ClinicalTrials.gov. Supplementary Information The online version contains supplementary material available at 10.1007/s00280-021-04294-2.

Effective therapies against metastatic pancreatic cancer remain limited, and despite treatment, many will ultimately progress. Previously, few options were available for second line therapy in metastatic pancreatic cancer. Liposomal encapsulated irinotecan, in combination with leucovorin-modulated fluorouracil, was found to significantly increase overall survival in patients who have progressed after gemcitabine- based therapy in a large, international, randomized clinical trial (NAPOLI-1). We reviewed the background of systemic therapy for metastatic pancreatic cancer, examined putative mechanisms for the success of encapsulated drugs, and identified recent patent applications on the use of liposomal irinotecan in pancreatic cancer. The landmark NAPOLI-1 trial established a second-line option for those with metastatic pancreatic cancer refractory to gemcitabine chemotherapy, but effective therapies with long duration of response are still lacking. Alternative techniques targeting key driver genes in pancreatic cancer and novel methods of early detection and targeting drugs are currently being explored. How liposomal irinotecan can be integrated into chemotherapy regimens, including neoadjuvant or first line combinations, are currently being tested in clinical trials and covered by several new patent applications.

392 Background: Pancreatic cancer remains one of the most lethal cancers in the United States (US) with a 5-year relative survival of 9%. Among patients who received liposomal irinotecan + 5-fluorouracil (5-FU) and leucovorin in the NAPOLI-1 study, a randomized phase 3 study in patients with mPDAC previously treated with gemcitabine-based therapy, 25% (n = 29) were alive at ≥ 1 year. This study examines the real world one-year survival of patients with mPDAC treated with liposomal irinotecan as a doublet with 5-FU in the NAPOLI-1 based regimen. Methods: This retrospective observational study utilized the Flatiron Health EHR database from over 280 cancer clinics in the US. Data were analyzed for adult patients with mPDAC treated with liposomal irinotecan-based regimens between November 2015 and July 2020. Patient characteristics and one-year overall survival (OS) based on Kaplan-Meier estimates were assessed. Cycles were defined as unique days with an administration of liposomal irinotecan. Results: There were 669 patients (median age: 69y, IQR: 62-75) included in the study. ECOG performance status (PS) of 0-1 and 2+ were reported for 78.3% (n = 396) and 21.7% (n = 110) of patients, respectively. ECOG PS was not captured for 24.4% (n = 163) of patients. 16.3% (n = 109) of patients initiated liposomal irinotecan-based in the first line (1L) metastatic setting, 47.5% (n = 318) in second line (2L), and 36.2% (n = 242) in the third line or later (3L+). The median number of cycles received was 4 (IQR: 2 – 8). Among all patients, one-year OS was 17.2% (95% CI: 14.3% - 20.7%). One-year OS was 31.5% (22.1% – 41.3%) for patients treated in 1L, 16.4% (12.2% - 21.1%) for patients treated in 2L, and 12.2% (7.5% - 18.0%) for patients treated in 3L. The median number of cycles for 1L, 2L, and 3L were 5, 4, and 3, respectively. One-year OS increased as patients were able to receive more cycles of liposomal irinotecan. Patients who received at least 2 cycles of liposomal irinotecan (n = 551) had a one-year OS of 20.4% (16.8% - 24.2%). Among patients who received at least 4 cycles (n = 359) and at least 8 cycles (n = 170), the one-year OS estimates were 29.1% (24.0% - 34.3%) and 47.9% (39.7% - 55.7%), respectively. Conclusions: In this real-world cohort of patients with mPDAC treated with liposomal irinotecan, as expected, one-year OS increased as patients remained on therapy. Patients in this cohort were older, had more prior lines of therapy, worse ECOG PS, and similar exposure to treatment compared with patients in the registrational phase 3 NAPOLI-1 study. Among patients who received at least 4 cycles of liposomal irinotecan, one-year OS (29%) was similar to both the intent-to-treat (25%) and per protocol treated patient populations in the NAPOLI-1 trial (34%). Further studies are needed to understand the predictors of long-term survival among patients with mPDAC.

TPS446 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 neoadjuvantly. Liposomal irinotecan injection (Nal-IRI) is FDA approved 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 II, 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 below 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 perioperative 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 postoperative complication rate. Clinical trial information: NCT03483038. [Table: see text]

382 Background: Liposomal irinotecan (nal-IRI) plus fluorouracil/leucovorin (5-FU/LV) has demonstrated its clinical benefit in patients with metastatic pancreatic adenocarcinoma (mPAC) who progressed on prior gemcitabine-based chemotherapy. However, its role in patients who previously treated with conventional irinotecan has not been investigated. We analyzed clinical outcomes of nal-IRI + 5-FU/LV in mPAC patients after progression on conventional irinotecan-containing chemotherapy. Methods: In this multicenter retrospective analysis, a total of 35 patients with mPAC who received nal-IRI + 5-FU/LV after progression on irinotecan-containing regimen, between January 2017 and March 2020, were included. The ratio of time-to-progression (TTP) with nal-IRI + 5-FU/LV to TTP with conventional irinotecan (TTPr) was correlated with duration and cumulative dose of prior conventional irinotecan. Results: The median age was 58 years (range, 35-73) and 16 patients (46%) were male. All patients received prior irinotecan as the component of FOLFIRINOX. The median duration of prior irinotecan was 4.6 months (range, 0.5-16.8) and median cumulative dose of prior irinotecan was 1230 mg (range, 150-4650). Objective response rate of nal-IRI + 5-FU/LV was 2.9% (1 partial response) and stable disease was achieved in 31.4% (n = 11). With median follow-up duration of 9.2 months [95% CI, 7.8-10.5], the median PFS and OS were 2.0 months [95% CI, 1.4-2.6] and 4.4 months [95% CI, 3.6-5.7], respectively. 6-month PFS rate was 16.3% and OS rate was 37.5%. The median TTPr was 0.41 (range 0.07-2.07) and this showed negative correlation between cumulative dose of prior irinotecan (R = -0.37, p = 0.041). There was a tendency for the negative correlation between TTPr and duration of prior irinotecan (R = -0.35, p = 0.062). Most common grade 3-4 toxicities were neutropenia (20%) and fatigue (8.6%). Conclusions: Nal-IRI + 5-FU/LV showed only modest efficacy for mPAC patients who progressed on conventional irinotecan-containing chemotherapy. Cumulative dose of prior conventional irinotecan may be correlated with the efficacy of nal-IRI + 5-FU/LV.

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.

The article Liposomal Irinotecan: A Review in Metastatic Pancreatic Adenocarcinoma, written by James E. Frampton, was originally published Online First without Open Access.

e16780 Background: Pancreatic cancer remains one of the most lethal cancers in the United States (US) with a 5-year relative survival of 10%. Liposomal irinotecan is a topoisomerase inhibitor indicated, in combination with 5-fluorouracil and leucovorin, for pts with mPDAC following disease progression on gemcitabine-based therapy. This study examines the real-world use and therapeutic management of pts with mPDAC treated with liposomal irinotecan. Methods: This retrospective observational study utilized the Flatiron Health EHR-derived de-identified database from over 280 cancer clinics in the US. Data were analyzed for adult pts with mPDAC treated with liposomal irinotecan based regimens between Nov 2015 and Oct 2019. Pts were categorized into two starting dose groups: 70mg/m2 and < 65mg/m2. Pt characteristics, overall survival (OS), duration of treatment (DOT), and impact of dose reductions (DR, reduction ≥ 7mg/m2) were assessed among pts who received ≥3 cycles of treatment (tx). Results: Of the 532 pts (median age: 69y, IQR: 62-75) included in the study, 95 (18%) had an ECOG score of 2+ at tx initiation. Of the 184 pts (69y, 42 – 84) that did not receive 3 cycles of tx, 47 (25%) had an ECOG score of 2+ and 83 (45%) had two or more prior lines of tx. 348 pts (69y, 43 – 85) received ≥3 cycles of tx. 116 (33%) pts had two or more prior lines of tx, 209 (60%) had an ECOG score of 0-1, 48 (14%) had an ECOG score of 2+, and 91 (26%) had missing scores. 220 (63%) initiated tx at 70mg/m2 and 128 (37%) initiated at < 65mg/m2. 83 (38%) 70mg/m2 and 26 (20%) < 65mg/m2 pts experienced a DR during tx. 43 (52%) and 14 (54%) of the DRs occurred within the first 6 wks of tx in the 70mg/m2 and < 65mg/m2 cohorts, respectively. Median DOT was 12.6 weeks for 70mg/mg2 and 9.1 wks for < 65mg/m2 pts; DOT was longer among pts with a DR: 19.0 wks and 16.1 wks, respectively. Median OS (mOS) was 7.2 months (95% CI: 6.2 – 8.1) and 6.2 mos (5.0 – 7.4) for pts receiving 70mg/m2 and < 65mg/m2, respectively. mOS for pts with a DR was 8.9 mos (7.3 – 10.8) and 7.7 mos (5.0 – 14.9) for pts receiving 70mg/m2 and < 65mg/m2, respectively. mOS for pts with no DR was 6.0 mos (4.8 – 7.2) and 6.0 mos (4.7 - 7.2) for those receiving 70mg/m2 and < 65mg/m2, respectively. Conclusions: In this descriptive study among pts who were able to receive ≥3 cycles of liposomal irinotecan and remain on tx for ≥4 wks, DRs were effective in extending DOT and OS, independent of starting dose. The longest DOT and OS were observed in the pts who received 70mg/m2 with DRs. Pts who received 70mg/m2 and < 65mg/m2 had similar OS in the absence of DRs.

e16740 Background: The goals of randomized control trials (RCTs) are to make causal inferences and precise treatment comparisons, not to describe large heterogeneous pt populations. RWE allows population-based healthcare decision makers to assess and manage therapeutic and economic options for their pts, including those who would and would not have met inclusion/exclusion criteria of a given RCT and are instead managed under usual care, irrespective of clinical trial protocols. In the pivotal phase 3 trial, NAPOLI-1, 117 pts were treated with liposomal irinotecan + 5-fluorouracil/folinic acid, median age 63 years; 66% were treated first- (1L) or second line (2L), and 91% had performance score ECOG 0 or 1. Pts in the trial had overall survival (OS) of 6.2 months (mos), time to treatment failure (TTF) 2.3 mos, and 27% experienced grades 3-4 neutropenia. The present study describes the patient characteristics and outcomes of pts with mPDAC treated with liposomal irinotecan in the US. Methods: This retrospective observational study used data from Flatiron Health EHR-derived de-identified database from over 280 cancer clinics. Patient characteristics, OS, TTF, and rates of neutropenia during treatment (tx) were assessed in adult pts diagnosed with mPDAC who received liposomal irinotecan based tx between November 1, 2015 and October 31, 2019. Results: 600 pts with mPDAC treated with a liposomal irinotecan based regimen were identified. Of these, 56% were initially diagnosed with stage IV disease, 53% were male, 21% had undergone a previous Whipple procedure, and 61% initiated liposomal irinotecan in the 1L or 2L metastatic setting. Median age at tx initiation was 68 (IQR: 62 – 75) years. 92% of pts were treated in the community setting. Among pts with available ECOG (n = 440), 77.5% were score 0-1. Grade 3/4 neutropenia was observed in 11% (n = 66). Overall, median OS was 5.0 mos [95%CI: 4.2–5.6]. mOS among pts treated in 1L (n = 88), 2L (n = 280), and third line plus (3L+, n = 232) were 6.9 mos [5.3–9.2], 5.4 mos [4.6–6.4], and 4.0 mos [3.4–4.5], respectively. Overall, median TTF was 1.9 mos [1.6–2.1]. TTF by line was 3.5 mos [2.3–4.8] in 1L, 2.1 mos [1.7–2.8] in 2L, and 1.4 mos [1.2–1.6] in 3L. Conclusions: This real-world cohort of pts with mPDAC were older, had worse performance status, and had more prior lines compared to the pivotal trial for liposomal irinotecan. Median OS, TTF, and neutropenia were similar to those previously reported. As expected, pts receiving liposomal irinotecan in earlier lines had higher median OS and TTF.

TPS4661 Background: Liposomal irinotecan administered with 5-fluorouracil/leucovorin (5-FU/LV) is approved in the USA for metastatic pancreatic ductal adenocarcinoma (mPDAC) following progression with gemcitabine-based therapy. A phase 1/2 study in previously untreated locally advanced/metastatic PDAC showed promising anti-tumor activity with liposomal irinotecan 50 mg/m2 free base + 5-FU 2400 mg/m2 + LV 400 mg/m2 + oxaliplatin (OX) 60 mg/m2 on days 1 and 15 of a 28-day cycle (Wainberg et al. Ann Oncol 2019;30 Suppl 4: SO-005). Herein, we present the design of the phase 3 NAPOLI-3 study investigating the efficacy and safety of this regimen as first-line therapy in patients with mPDAC. Methods: NAPOLI-3 (NCT04083235) is a phase 3, open-label, randomized, global study in adults with histologically/cytologically confirmed pancreatic adenocarcinoma not previously treated in the metastatic setting. Patients are required to have one or more metastatic tumors measurable with computed tomography/magnetic resonance imaging and an Eastern Cooperative Oncology Group performance status score of 0–1. Site activation began in Dec 2019 and enrollment is ongoing. Random allocation (1:1) of 750 patients is planned to liposomal irinotecan + 5-FU/LV + OX (regimen as per phase 1/2 study) or nab-paclitaxel 125 mg/m2 + gemcitabine 1000 mg/m2 on days 1, 8 and 15 in a 28-day cycle. The primary endpoint is overall survival (OS). Secondary endpoints (progression-free survival [PFS] and overall response rate assessed with Response Evaluation Criteria in Solid Tumors v1.1 criteria) will be compared only if the primary endpoint shows superiority for liposomal irinotecan + 5-FU/ LV + OX over nab-paclitaxel + gemcitabine. Safety assessments include adverse-event monitoring. Patients will continue treatment until disease progression, unacceptable toxicity or study withdrawal, and will then be followed for survival every 2 months until death or study end (when all patients have died, withdrawn consent or are lost to follow-up). Clinical trial information: NCT04083235 .

e16733 Background: Real-world data allows healthcare decision-makers to assess and manage therapeutic and economic options for patients, including those who would and would not have met eligibility criteria for randomized control trials (RCT) and are instead managed under usual care. This retrospective multi-academic center chart review study describes real-world characteristics and outcomes of US patients receiving liposomal irinotecan for the management of metastatic pancreatic ductal adenocarcinoma (mPDAC). Methods: Patients with mPDAC treated with liposomal irinotecan were eligible. Initiation of liposomal irinotecan defined index date; covariates assessed included clinical characteristics and treatment patterns; real-world overall survival (rwOS) was assessed via Kaplan-Meier methodology. The target enrollment is 300 patients. The study centers included were Memorial Sloan Kettering Cancer Center, Cedars-Sinai Medical Center, Emory Winship Cancer Institute, Houston Methodist Cancer Center, Henry Ford Cancer Institute, and University of Pittsburgh Medical Center. Results: Data on 26 patients were available for initial analyses. Mean age was 68 years; 58% were female and 65% Caucasian. 54% of patients had stage IV disease at first diagnosis, and 17%, 65%, and 17% had index ECOG score of 0, 1, and 2, respectively. Common genetic mutations include KRAS (40%) and TP53 (40%). Prior to liposomal irinotecan, treatments received for metastatic disease include gemcitabine+nab-paclitaxel (77%) and fluorouracil (5-FU)/leucovorin (LV)+irinotecan+oxaliplatin (19%). Patients had received 0 (12%), 1 (23%), and ≥2 (65%) lines of therapy in the metastatic setting prior to liposomal irinotecan. Mean duration of liposomal irinotecan use was 3.0 months; liposomal irinotecan was mostly received with 5-FU (23%) or 5-FU/LV (69%). Median rwOS was 4.9 months (95% CI: 3.0, 6.3). Conclusions: Real-world data of the first 26 patients in this study show patients treated with liposomal irinotecan are older, sicker, and have had more lines of therapy than previously reported in RCT data.

e16724 Background: Liposomal irinotecan (ONIVYDE) is approved with 5-fluorouracil/leucovorin for metastatic pancreatic ductal adenocarcinoma (PDAC) post progression on gemcitabine-based therapy. The liposomal formulation prolongs payload residence time in the circulation and tumor lesions, where local conversion to the active metabolite SN-38 is thought to occur. The effect of the liposomal formulation on therapeutic index (TI) was assessed in patient-derived xenograft PDAC models (IM-PAN-001 [untreated tumor] and SA-PAN-077) in severe combined immunodeficiency mice. Methods: Liposomal (2.5, 10 or 50 mg/kg, intravenous [IV] 1 x weekly) and non-liposomal irinotecan (2, 5 or 10 mg/kg, IV 5 x weekly) were administered for 3 weeks (n = 8/group). Maximum tolerated dose (MTD) and clinically-relevant weekly doses (10 mg/kg, liposomal; 33 mg/kg, non-liposomal) of irinotecan were evaluated. TI was the ratio of MTD/lowest dose with anti-tumoral activity; time to reach tumor volume of 600 mm3 (TTV600) was a proxy for overall survival. Tumor, plasma, gut and bone marrow were sampled for pharmacokinetics and safety assessment; DNA damage was evaluated via pH2AX and 53BP1 IHC. Results: The Table reports results of the more sensitive IM-PAN-001 model: TI of weekly liposomal irinotecan was 4-fold higher than for 5 x weekly non-liposomal irinotecan (TI was narrower for SA-PAN-077). For liposomal vs non-liposomal irinotecan in IM-PAN-001, TTV600 was longer at both MTD and clinically equivalent doses, and tumoral irinotecan levels were higher at MTD. High levels of DNA damage were present in most cancer cells in IM-PAN-001 compared to SA-PAN-077 one week after the last liposomal treatment cycle. Conclusions: In both PDAC models, TI was higher for weekly liposomal vs 5 x weekly non-liposomal irinotecan, suggesting potential benefits of the liposomal formulation in a clinical setting. [Table: see text]

9069 Background: Most patients with extensive SCLC develop drug resistance to platinum-based 1L therapy or discontinue for other reasons, and second-line (2L) therapies are limited. RESILIENT (NCT03088813) is a two-part phase 2/3 study assessing the safety, tolerability and efficacy of 2L liposomal irinotecan monotherapy in adults with SCLC who progressed with platinum-based 1L therapy. Preliminary data from RESILIENT part 1 (cut-off May 8 2019; ≥ 12 weeks follow-up) showed that liposomal irinotecan 70 mg/m2 free base every 2 weeks was generally well tolerated and had encouraging antitumor activity (Paz-Ares et al. WCLC 2019 OA03.03). Objective response rate (ORR; secondary endpoint) was 44% (11/25). Here we report efficacy analyses in post hoc subgroups by platinum sensitivity. Methods: RESILIENT part 1 was an open-label, single-arm study comprising dose-finding and dose-expansion phases. Eligible patients were aged ≥ 18 y, with an ECOG performance status score of 0/1 and adequate organ function; a single line of prior immunotherapy was allowed. Participants received liposomal irinotecan 70 mg/m2 or 85 mg/m2 free base every 2 weeks, with tumor assessments every 6 weeks (RECIST v1.1). Analyses were undertaken for the dose-finding phase recommended dose (RD) in subgroups of platinum-resistant/sensitive patients (with/without progression within 90 days from completion of 1L therapy). Results: During dose finding, 5 patients received liposomal irinotecan 85 mg/m2 (deemed not tolerable; dose-limiting toxicity) and 12 received 70 mg/m2 (deemed tolerable; RD for dose-expansion phase in which 13 more patients were included). Analyses included all 25 patients receiving the RD (mean exposure, 13.95 weeks [median 14.86; SD 7.222]). In the platinum-sensitive subgroup (33.3% men; median age 62.0 y) ORR was 53.3% (8/15) and 12-week disease control rate (DCR12wks) was 60% (9/15); in the platinum-resistant subgroup (50% men, median age 58.0 y) both ORR and DCR12wks were 30% (3/10). Overall and progression-free survival (secondary endpoints) are not yet mature. Conclusions: ORR and DCR12wks were numerically higher in platinum-sensitive than in platinum-resistant patients with SCLC who had progressed with platinum-based 1L therapy before receiving 2L liposomal irinotecan 70 mg/m2 in this phase 2 study. RESILIENT part 2, an ongoing, phase 3, randomized controlled trial vs topotecan, will provide further data. Clinical trial information: NCT03088813.

e16751 Background: The NAPOLI-1 study, a randomized phase 3 study in pts with mPDAC previously treated with gemcitabine-based therapy, demonstrated an improvement in overall survival (OS) with liposomal irinotecan + 5-fluorouracil/ leucovorin (5-FU/LV) vs. 5-FU/LV. In this analysis we describe the trends in pt characteristics, real-world OS (rwOS), and real-world time to-treatment failure (rwTTF) among pts with mPDAC treated with liposomal Irinotecan based regimens overall and stratified by tx initiation prior to 2018 (pre-2018) or after 2018 (post-2018). Methods: This retrospective observational study used de-identified data from Flatiron Health EHR database from over 280 cancer clinics in the US. Pt characteristics, rwOS, and rwTTF were assessed in adult pts diagnosed with mPDAC who received liposomal irinotecan treatment (tx) between January 1, 2016 and October 31, 2019. Results: Of the 590 pts treated with liposomal irinotecan based regimens, 53% were male, 56% were initially diagnosed with Stage IV disease, 92% were treated in the community setting, and median age at tx initiation was 69 (IQR: 62 – 75) years. Among pts with available ECOG scores (N = 435), 77% had a score of 0 or 1. 43% (n = 254) initiated tx pre-2018 and 57% (n = 336) post-2018. Pre-2018, 106 (42%) pts initiated liposomal irinotecan in the third line metastatic setting or later (3rd line+), 125 (49%) had ECOG score of 0-1, and median age was 68 (62–74) years. Post-2018, 36% of pts initiated tx in 3rd line+, 211 (63%) had ECOG score of 0-1, and median age was 70 (63 – 75) years. Median rwOS was 4.4 months [95% CI: 4.3–6.2] pre-2018 and 5.2 mos [4.3–6.2] post-2018. rwTTF was 1.6 mos [1.4–1.9] pre-2018 and 2.1 mos [1.6–2.5] among pts post-2018. Among pts treated in first- or second-line, pre-2018 rwOS was 5.3 mos [3.9–6.4] and post-2018 rwOS was 6.3 mos [5.0– 7.6]. Conclusions: In this descriptive real-world study of pts with mPDAC receiving liposomal irinotecan based regimens, pts initiating treatment post-2018 appear to be less pre-treated, older, and have better performance status than pts pre-2018. Pts treated post-2018 experienced numerically longer rwTTF and rwOS than pts treated pre-2018.

TPS9081 Background: Although small cell lung cancer (SCLC) is often sensitive to established first-line therapies, many patients relapse and develop drug resistance, and second-line therapies are limited. RESILIENT (NCT03088813) is a two-part phase 2/3 study assessing the safety, tolerability, and efficacy of liposomal irinotecan monotherapy in patients with SCLC who progressed with platinum-based first-line therapy. Preliminary data from the dose-ranging part of the study (part 1) showed that liposomal irinotecan 70 mg/m2 administered every 2 weeks was well tolerated and had promising antitumor activity (Paz-Ares et al. ASCO 2019; poster 318). Here, we present the design of the second, larger part of the study, which will evaluate the efficacy and safety of liposomal irinotecan versus topotecan in the same patient population. Methods: Part 2 of RESILIENT is a phase 3, open-label study with a planned sample size of 450. Patients are randomly allocated 1:1 to intravenous liposomal irinotecan or intravenous topotecan. Liposomal irinotecan is administered every 2 weeks at 70 mg/m2 (free-base equivalent) and topotecan is administered for 5 consecutive days every 3 weeks at 1.5 mg/m2. As of January 2020, 80 patients have been enrolled in part 2 of the trial. Tumor assessments are performed using the Response Evaluation Criteria in Solid Tumors version 1.1 and the Response Assessment in Neuro-oncology criteria for CNS lesions; symptom improvement is measured using the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire Core 30. Safety assessments include monitoring for adverse events. The primary endpoint is overall survival (OS) and secondary endpoints are progression-free survival (PFS), objective response rate, and proportion of patients reporting symptom improvement. Patients will continue study treatment until disease progression, unacceptable toxicity or study withdrawal and will then be followed for survival until death or study end (when all patients have died, withdrawn consent or are lost to follow-up). Clinical trial information: NCT03088813.

4624 Background: There is no clear consensus on the second-line treatment for patients with metastatic pancreatic cancer (mPC). The aim of this study was to compare the efficacy and tolerability between liposomal irinotecan (nal-IRI) plus fluorouralcil/leucovorin (FL) and FOLFIRINOX (oxaliplatin/irinotecan/leucovorin/fluorouracil) in patients who failed to first-line gemcitabine-based therapy. Methods: In this retrospective study, 378 mPC patients who received nal-IRI/FL (n = 104) or FOLFIRINOX (n = 274) as the second-line treatment across 11 institutions from January 2015 to August 2019 were analyzed. The primary end point was progression free survival (PFS), and secondary end points were overall survival (OS), overall response rate, and tolerability. Results: There were no significant differences between the two groups in terms of baseline characteristics, except first-line regimen (previous gemcitabine/nab-paclitaxel, nal-IRI/FL, 85.6% vs. FOLFIRINOX, 51.5%; previous gemcitabine monotherapy, 5.8% vs. 24.5%). The median follow-up time was 6.0 months. The median PFS (nal-IRI/FL, 3.7 months vs. FOLFIRINOX, 5.0 months) and OS (nal-IRI/FL, 7.7 months vs. FOLFRINOX, 9.7 months) were comparable between two groups (P = 0.40 and 0.13, respectively). The overall response rate was not significantly different between two groups (nal-IRI/FL, 14% vs. FOLFRINOX, 16%; P = 0.644). In multivariate analysis, poor ECOG status, presence of liver metastasis, high NLR, and high CA19-9 were independent prognostic factors for PFS and OS, but chemotherapy regimen (nal-IRI/FL vs. FOLFRINOX) was not. In a subgroup analysis of patients with liver metastasis, FOLFIRINOX exerted significant PFS (median: 2.1 months vs. 4.1 months for nal-IRI/FL vs. FOLFIRINOX, respectively; P = 0.02) and OS (median: 6.7 months vs. 8.4 months for nal-IRI/FL vs. FOLFIRINOX, respectively; P = 0.04) benefit compared with nal-IRI/FL. Grade 3 neutropenia or higher were more frequently observed in FOLFIRINOX (47.2%) than nal-IRI/FL (35%) (P = 0.033). Grade 3 peripheral neuropathy was also common in FOLFIRIONX (5.9%) group compared with nal-IRI/FL (1.0%) (P = 0.049). Conclusions: In second-line setting for mPC after progression on gemcitabine-based therapy, both nal-IRI/FL and FOLFIRINOX regimen showed comparable efficacy and acceptable safety outcomes. FOLFIRINOX regimen might be preferentially considered in patients with liver metastasis.

660 Background: In the NAPOLI I phase III trial, Nanoliposomal irinotecan (nal-IRI) plus 5-fluorouracil/leucovorin (5-FU/LV) showed better outcome compared to 5FU/LV in patients with metastatic Pancreatic Cancer (MPC) progressed to 1st- line gemcitabine-based therapy. Aim of this study is to explore the real-world efficacy and safety of 5FU/LV-nal-IRI by a compassionate use programme and to identify potential prognostic factors that could affect survival in this setting. Methods: This is a retrospective multi-center analysis including patients with MPC who received 5FU/LV-nal-IRI after failure of a gemcitabine-based therapy. Survival analyses were carried out by the Kaplan-Meier method. Univariate and multivariate analyses were performed by using the log-rank test and the Cox regression. Results: A total of 296 pts (median age, 69 years, range 30-82; 50% male; ECOG PS 0, 44%) were treated at 11 Italian institutions from June 2016 and November 2018. 34% of the pts have been previously resected on their primary tumor, and 76% received gemcitabine-nabpaclitaxel as 1st - line treatment. 5FU/LV-nal-IRI has been administered as 2nd - line in 72% of the pts, while in 23% of the cases as 3rd - line or more. The median OS was 7.1 months [95% confidence interval (CI) 6.1 - 8.1] and the median PFS was 3.3 months (95% CI 2.9 - 3.6). At six months, OS and PFS rate were 53.4% and 31.4% respectively. ORR was 12% and DCR was 40%. 52% of pts received more than 4 cycle with dose reduction in 148 pts (50%). Most common grade 3 toxicities were neutropenia (14%), diarrhea (11%), anemia (3%), nausea (3%), fatigue (3%), mucositis (2%) and vomiting (1%). Baseline characteristics associated with better OS were ECOG PS 0, normal CEA, neutrophil-to-lymphocyte ratio ≤5 and haemoglobin ≥11 g/dL. Conclusions: These real-world data confirm the efficacy and safety of 5FU/LV-nal-IRI in patients with MPC progressed to a gemcitabine-based therapy, with outcome comparable to NAPOLI-1 even in a less selected population and with more active 1st - line combination therapy. In this cohort, well known prognostic markers has been confirmed, as expected.

TPS793 Background: Pancreatic ductal adenocarcinoma (PDAC) is predicted to be the second leading cause of cancer-related death by 2030, and is characterized by resistance to chemo- and radiotherapy and a highly fibrotic tumor microenvironment. Front-line therapies for advanced PDAC include FOLFIRINOX and gemcitabine/nab-paclitaxel with median overall survival ranging from 8.5 to 11 months. After progression on gemcitabine-containing therapy, 5-FU/LV/liposomal irinotecan is a standard second-line option, however outcomes are still poor. Retrospective studies demonstrate superior survival of advanced PDAC in patients with high serum levels of 25(OH) vitamin D. Notably, the PDAC tumor microenvironment is enriched in cancer-associated fibroblasts that favorably respond to vitamin D, prolonging survival in combination with chemotherapy in mouse models. Furthermore, vitamin D suppresses catabolism of irinotecan in gastrointestinal cancer cells, potentiating its efficacy. Therefore, we are conducing an investigator-initiated study of 5FU/LV/liposomal irinotecan with paricalcitol as second-line therapy in advanced PDAC. Methods: This is a pilot study of 5FU/LV/liposomal irinotecan combined with paricalcitol in patients with advanced PDAC progressed on gemcitabine-based therapy. All patients receive liposomal irinotecan, LV, 5-FU and paricalcitol. Liposomal irinotecan is given at 70 mg/m2 IV over 90 minutes, LV at 400 mg/m2 IV over 30 minutes, and 5-FU at 2400 mg/m2 continuous IV infusion over 46 hours, on Day 1 of each 14-day cycle. Paricalcitol IV infusion will precede the above, given according to assigned cohort (75 mcg weekly or 7 mcg/kg weekly). The primary objective of this study is to determine the tolerability between two different dose levels of paricalcitol added to the combination regimen of 5-FU/LV/liposomal irinotecan in patients with advanced PDAC. Secondary objectives are measures of efficacy (ORR, PFS, OS, CA19-9 biochemical response rate). Clinical trial information: NCT03883919.

667 Background: Published data suggests prior exposure to irinotecan infers a lower likelihood of benefit to liposomal irinotecan. This analysis seeks to expand this hypothesis by evaluating U.S. patterns of care to understand how prior irinotecan therapy impacts outcomes in mPC. Methods: Using the Flatiron Health database, data were extracted and analyzed for treated mPC patients (pts) in the 2L+ setting between Jan 1, 2014 and Jun 30,2019. Therapies of interest included: gemcitabine/ nab-paclitaxel (GnP), FOLFOX, FOLFIRI, FOLFIRINOX (FFX), and liposomal irinotecan/5-FU/LV (nal-IRI). The reference date for each treatment group was the date of treatment initiation. Prior irinotecan was defined as any irinotecan given in a prior regimen in mPC diagnosis. Cox proportional hazard (PH) methods were used to calculate mortality hazard ratios (HRs). HRs were adjusted to account for demographics and relevant covariates. Pts with prior exposure to irinotecan were used as the reference population for the Cox PH model (an HR < 1 represents worse survival for exposed pts relative to the unexposed). Results: N = 1,978 were included in this analysis. The median age at treatment initiation, and the proportion of pts previously treated with irinotecan are reported in table. Crude mortality was: GnP pts, HR 0.93 [95% CI: 0.77 – 1.11, adjusted HR, 0.94, 0.76 – 1.15]; nal-IRI pts, HR 0.81 [0.64 – 1.02, adjusted HR: 0.89, 0.67 – 1.19]; HR for FOLFOX was 0.55 [0.38 – 0.78, adjusted HR: 0.51, 0.33 – 0.79]. HRs are not reported for FFX and FOLFIRI due to the small numbers with prior irinotecan exposure. Conclusions: In mPC, prior irinotecan treatment may not preclude benefit from later treatment with nal-IRI or GnP as can be seen from the adjusted and unadjusted HRs. These findings are hypothesis-generating and need to be considered in the context of wide CI’s, retrospective nature and the limitations of such data. Further study is required to understand the less-favorable signal observed with FOLFOX and prior irinotecan.[Table: see text]

665 Background: The recommended starting dose for nal-IRI is 70mg/m2 (free base, equivalent to 80 mg/m2 salt-based dosing). This study evaluates the impact of nal-IRI dose reductions on clinical outcomes. Methods: Using the nationwide Flatiron Health electronic health record-derived database, de-identified data were extracted and analyzed for adult mPC pts treated with nal-IRI Jan 2014-Jan 2019 and who initiated treatment at approximately the recommended dose (RD), 70mg/m2 +/- 5mg. Initial dose was derived from structured medication records, prioritizing administrations. The cumulative dose (CD) of nal-IRI over the first six weeks of treatment, the presence of dose reductions (DR) – (a decrease ≥ 7mg/m2), overall survival (OS) from treatment initiation, and duration of treatment (DoT) were assessed. Results: 257 mPC pts treated with nal-IRI (median age: 68y, IQR: 61 - 73) were identified initiating therapy at approximately the RD. 26.5% (N = 68) of pts experienced a DR during treatment. Mean 6-week CD was 175.8 mg/m2 (SD: 77.9) among pts with no DR. For pts with DR, mean CD was 191.8 mg/m2 (53.2). Median DoT was 6.1 wks (IQR: 2.1 – 15.3). Pts that experienced a DR had a longer median DoT: 15.1 wks (7.1 – 23.0) vs 4.3. wks (2.1 – 12.1) for pts with no DR. Overall Median OS (mOS) was 4.2 months (95% CI: 3.7 – 5.4). mOS for DR pts was 7.2 mos (95% CI: 5.5 – 9.7) and 3.7 mos (3.0 – 4.1) for pts who did not experience a DR. Conclusions: This real-world analysis suggests that reducing the dose of subsequent administrations of nal-IRI during treatment is associated with pts remaining on therapy longer, experiencing a larger CD, and a with longer OS. Additional real-world prospective studies are necessary to characterize the impact of nal-IRI dosing on clinical outcomes.

BACKGROUND: Chemotherapy for high grade gliomas (HGG) is limited by the blood-brain-barrier (BBB). Convection enhanced delivery (CED) improves chemotherapy delivery by utilizing fluid convection obviating the challenges of crossing the BBB while minimizing systemic toxicity. CED of nanoliposomal-irinotecan (Onivyde) showed to be a superior delivery route for anti-tumor activity in animal models. An advance of this trial is the development and use of real time CED, which utilizes MRI to visualize the CED process with the aid of co-convected contrast agents, monitoring delivery into the brain and affording for corrective action. METHODS: This is a 3 + 3 single dose escalation trial with 2 cohorts: 20mg/ml and 40mg/ml. Onivyde and GAD were co-infused via the same catheters in a one-time delivery. The total volume of infusate, and consequently total dose, were personalized based on the patient’s tumor volume, and ranged from 20–680 mg of Onivyde, given via up to 4 catheters. Tumor diameters were allowed to be 1 – 4 cm, with injection volumes ranging from 2 – 17 mL of infusate. RESULTS: 10 patients have been treated on this protocol, all in under 5 hours. There were 7 GBs, 2 anaplastic astrocytomas, and 1 oligoastrocytoma. Seven patients lived over a year after treatment, which is remarkable since median survival rates for multiply recurrent: GBs = 8 months, AAs = 11 months. Utilizing imaging software, we correlated pre-infusion modeling of the drug distribution with post-infusion imaging. A number of technical challenges were overcome by real time monitoring; the total volume of distribution (Vd), and the Vd to volume infused (Vi) ratio for each infusion was ~2. CONCLUSIONS: Image-guided distribution allows for safe real-time placement and adjustment of CED cannula of Onivyde into patient’s brains. Such methods allow for maximum tumor coverage and warrant further studies with repeat dosing.