New Standard of Care Proposed for Metastatic Pancreatic Cancer

Journal Abstracts published on June 13, 2016
New Standard of Care Proposed for Metastatic Pancreatic Cancer

Despite first-line treatment with gemcitabine-based therapies as the standard of care for patients with metastatic pancreatic ductal adenocarcinoma, there is no universally accepted standard treatment for patients who progress. The purpose of the phase III, open-label, multicenter, international NAPOLI-1 (Nanoliposomal Irinotecan with Fluorouracil and Folinic Acid in Metastatic Pancreatic Cancer After Previous Gemcitabine-based Therapy) trial was to assess the efficacy and safety of nanoliposomal irinotecan (Nal-IRI), alone or in combination with fluorouracil and folinic acid (5FU/LV), compared to a 5FU/LV control, in patients with metastatic pancreatic ductal adenocarcinoma previously treated with gemcitabine-based therapy.

Patients with locally advanced or metastatic disease, Karnofsky performance status ≥70 and adequate hematologic, hepatic and renal function, were assigned 1:1:1 to Nal-IRI + 5FU/LV, Nal-IRI monotherapy or 5FU/LV control. (Table 1)

Table 1. Dosing Schedule of Nal-IRI + 5FU/LV, Nal-IRI Monotherapy, 5FU/LV Control

Study Arm

Dosing Schedule

Nal-IRI + 5FU/LV

Nal-IRI 80 mg/m2 IV over 90 min, then LV 400 mg/m2 IV over 30 min, then 5FU 2400 mg/m2 over 46 hrs; every 2 weeks

Nal-IRI Mono

Nal-IRI 120 mg/m2 IV over 90 min every 3 weeks

5FU/LV Control

LV 200 mg/m2 IV over 30 min, then 5FU 2000 mg/m2 over 24 hrs every week for the first 4 weeks of each 6-week cycle

After 313 deaths, the primary endpoint, median overall survival (OS) was met. Nal-IRI + 5FU/LV demonstrated a 33% reduction in the risk of death compared to 5FU/LV (HR 0.67; 95% CI 0.49, 0.92; P=.012); the median OS was 6.1 months (95% CI: 4.8, 8.9) versus 4.2 months (95% CI: 3.3, 5.3) in the Nal-IRI + 5FU/LV and 5FU/LV treatment arms, respectively. Nal-IRI + 5FU/LV demonstrated a benefit in progression-free survival, median time to treatment failure, objective response rates and CA19-9 biomarker response, compared to 5FU/LV. There was no significant difference between quality of life (QoL) measures and clinical benefit response between the two groups. There was no difference in median OS between Nal-IRI monotherapy and 5FU/LV control (HR 0.99; 95% CI: 0.77, 1.28; P=.94).

The most common Grade 3/4 adverse events in the Nal-IRI + 5FU/LV, Nal-IRI monotherapy and 5FU/LV control include: diarrhea (13% vs. 21% vs. 4%), vomiting (11% vs. 14% vs. 3%), fatigue (14% vs. 6% vs. 4%), and neutropenia (27% vs. 15% vs. 1%). Grade 3/4 neutropenic sepsis occurred in 3% and 4% of patients treated with Nal-IRI + 5FU/LV and Nal-IRI monotherapy, respectively; there were no cases in the 5FU/LV control group.

The addition of Nal-IRI to 5FU/LV demonstrated an improvement in survival benefit and clinical efficacy outcomes compared to 5FU/LV alone. There was no difference between Nal-IRI monotherapy and 5FU/LV, supporting the use of combination therapy. Patients with a Karnofsky score <90, albumin concentration <40 g/L, CA19-9 >40 IU/mL and liver metastases, had an increased OS when treated with Nal-IRI + 5FU/LV, suggesting use of combination therapy in this patient population.

The QoL did not differ between study arms, despite the increase in toxicity experienced by patients treated with Nal-IRI + 5FU/LV and Nal-IRI monotherapy. Although the Nal-IRI + 5FU/LV arm received a lower dose per cycle and lower observed mean dose intensity compared to Nal-IRI monotherapy, the incidence of Grade 3/4 neutropenia was higher; this may be attributed to the addition of 5FU/LV. Interestingly enough, the incidence of gastrointestinal events was lower in the Nal-IRI + 5FU/LV group, compared to Nal-IRI monotherapy.

The combination of Nal-IRI + 5FU/LV demonstrated improved outcomes with manageable toxicity for patients with metastatic pancreatic ductal adenocarcinoma. The National Comprehensive Cancer Center currently recommends (Category 1) Nal-IRI + 5FU/LV as second-line treatment for patients with metastatic disease previously treated with gemcitabine-based therapy. However, future studies are needed to determine the value of Nal-IRI + 5FU/LV therapy in sicker patients (Karnofsky score <70 and albumin <30 g/L) and after first-line FOLFIRINOX, as there were few patients with prior IRI enrolled in the study.

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Last modified: June 2, 2016

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