Results from a retrospective, observational analysis examining the real-world dosing patterns of patients with metastatic pancreatic cancer (mPC) treated with irinotecan liposome injection (Onivyde?, Ipsen Biopharmaceuticals, an affiliate of Ipsen) shows that in a real-world setting patients experienced similar dosing patterns as seen in the pivotal Phase III NAPOLI-1 clinical trial.

The results were presented in a poster presentation at this year?s annual meeting of the European Society for Medical Oncology – ESMO 2018, being held in Munich, Germany, Oct. 19-23, 2018.

Pancreatic cancer is a rare and deadly disease with about 55,440 people (29,200 men and 26,240 women) being diagnosed with pancreatic cancer in the United States alone.[1] More than half are diagnosed with metastatic disease, which has an overall 5-year survival rate of less than three percent (3%) [1], and often rapidly progresses during or shortly after receiving chemotherapy.[2] Pancreatic cancer accounts for about 3% of all cancers, and is the third leading cause of cancer-related death in the United States, surpassing breast cancer.[1] It is expected to become the second leading cause of cancer-related death in the U.S. by the year 2030, surpassing colorectal cancer.[1][3]


This real-world data analysis provides further evidence in support of the dose intensity and duration of exposure of irinotecan liposome injection and 5-FU/LV observed in the NAPOLI-1 phase III trial


Irinotecan liposome injection, an encapsulated formulation of irinotecan, is a long-circulating liposomal form of the drug designed to increase length of tumor exposure to both irinotecan and its active metabolite, SN38.[4][5] It is indicated in combination with fluorouracil and leucovorin for the treatment of patients with metastatic adenocarcinoma of the pancreas that has progressed following gemcitabine-based therapy and approved by the U.S. Food and Drug Administration (FDA), the European Medicine Agency (EMA) and other regulatory bodies.[4]

Trial vs. Real-World data
Using the Flatiron Health electronic health record (EHR)-derived database, a longitudinal and nationally representative database comprising patient-level structured and unstructured data that is curated via technology-enabled abstraction, researchers identified 257 metastatic pancreatic cancer patients (median age: 67y; IQR: 61?74) who received ONIVYDE + fluorouracil (5-FU) and leucovorin (LV) therapy between November 2015 to August 2017 and analyzed their treatment data to assess dose intensity (DI) over the first 6 weeks of treatment, dose modifications during treatment, and overall duration of exposure (DOE) to irinotecan liposome injection.

Image 1.0: Overall mean Dose Intensity was 177.8 mg/m2 (SD 74.9 mg/m2) with median Dose Intensity for subgroups shown. When stratified into groups based on median Dose Intensity (190 mg/m2), more patients below (<) median Dose Intensity initiated at a low dose compared to those at or above (?) median Dose Intensity (44.4% vs 13.8%, respectively).

Analyses
The real-world analysis describes how irinotecan liposome injection was incorporated in the treatment sequencing that contained prior gemcitabine in the treatment of metastatic pancreatic cancer. In this analysis, the mean dose intensity was 177.8 mg/m2 (SD: 74.9 mg/m2). The median dose at initiation was?69.4 mg/m2 (IQR: 56.7?70.2); the recommended dose for irinotecan liposome injection is 70 mg/m2. In addition, median duration of exposure was 8.9 weeks (IQR: 3.9/19 weeks) in first and second line and 6.3 weeks (IQR: 3.4/12.1 weeks) in third or plus lines.

These results are generally consistent with the NAPOLI-1 trial, however, dose modifications in the real-world analysis were lower (27.2% vs 45% in NAPOLI-1). In the NAPOLI-1 phase 3 trial, dose intensity over 6 weeks and duration of exposure for combination therapy with irinotecan liposome injection was 167.5 mg/m2 (SD 44.8) and 8.7 weeks (IQR: 5.4 ? 22.0), respectively. Despite these real-world patients being older, having worse performance status and more prior lines of treatment than patients in NAPOLI-1, more than half (59.1%) of patients started irinotecan liposome injection + 5-FU/LV treatment with the recommended irinotecan liposome injection dose (70 mg/m2).

Trial
NAPOLI-1 is the largest global, phase III, randomized, open-label, multicenter trial in patients (N=417) with metastatic pancreatic cancer whose disease had progressed following gemcitabine-based therapy. Patients in the NAPOLI-1 trial being treated with irinotecan liposome injection in combination with fluorouracil (5-FU) and leucovorin (LV) had improved overall survival (OS; primary endpoint) vs 5-FU/LV (6.1 mos vs 4.2 mos; HR = 0.67, 95% CI 0.49?0.92; P = 0.012). irinotecan liposome injection ?monotherapy had no effect on OS.

Adverse events
Irinotecan liposome injection can cause severe, life-threatening neutropenia and diarrhea. The drug can also cause severe and fatal Interstitial Lung Disease (ILD) and hypersensitivity reactions. These serious adverse events may require withholding or discontinuing treatment with Irinotecan liposome injection, a dose reduction and/or supportive treatment. The most common adverse reactions in NAPOLI-1 (?20%) were diarrhea (59%), fatigue/asthenia (56%), vomiting (52%), nausea (51%), decreased appetite (44%), stomatitis (32%), and pyrexia (23%).

?Patients are at the heart of what we do, with unmet need guiding our development strategy and driving how we innovate for patient care,? said Sotirios Stergiopoulos, MD, Senior Vice President, Head of Global Medical Affairs and Chief Medical Officer.

?This real-world data analysis provides further evidence in support of the dose intensity and duration of exposure of irinotecan liposome injection and 5-FU/LV observed in the NAPOLI-1 phase 3 trial. This retrospective analysis allows us to further understand how patients with pancreatic cancer are receiving and managing their treatment in real-world settings,? Stergiopoulos added.

“As a physician who treats patients with metastatic pancreatic cancer, I find it reassuring and welcome the unique evidence the Flatiron dosing analysis provides in demonstrating the real-world usage of irinotecan liposome injection + 5-FU/LV in a large sample of metastatic pancreatic cancer patients being treated in a clinical oncology setting when compared to a clinical trial setting,” noted Afsaneh Barzi, MD Study Investigator, Norris Comprehensive Cancer Center, University of Southern California, Los Angeles, California.

“Data from our real-world practice for clinical analysis serve to further our knowledge about how to continue to effectively treat our patients,” he concluded.

Clinical trial
Study of MM-398 With or Without 5-FU/LV, Versus 5-FU/LV in Patients With Metastatic Pancreatic Cancer (NAPOLI-1) – NCT01494506

References
[1] Key Statistics for Pancreatic Cancer. American Cancer Society. https://www.cancer.org/cancer/pancreatic-cancer/about/key-statistics.html. Published January 4, 2018. Accessed October 20, 2018
[2] Ammermann et al. Decision Resources. Disease Landscape and Forecast: Pancreatic Cancer. June 2016.
[3] Rahib L, Smith BD, Aizenberg, et al. Projecting cancer incidence and deaths to 2030: the unexpected burden of thyroid, liver, and pancreas cancers in the United States. Cancer Res. 2014 Jun 1;74(11):2913-21. doi: 10.1158/0008- 5472.CAN-14-0155.
[4] Baker DE, Levien TL Irinotecan Liposome Injection Hosp Pharm. 2017 Feb; 52(2): 144?150.doi: 10.1310/hpj5202-144
[5] Onivyde (irinotecan liposome injection) [prescribing information]. Cambridge, MA: Merrimack Pharmaceuticals Inc.; October 2015.


Last Editorial Review: October 22, 2018

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