Liposomal Pegylated Irinotecan in the Treatment of Pancreatic Tumors

Challenges in the Treatment of Pancreatic Tumors

The median survival of patients with malignant pancreatic tumors ranges from 1 to 6 months (according to an analysis of 12 observational studies, the median is 4.6 months). Approximately 10-23% of patients survive 1 year after diagnosis. For patients with advanced or metastatic disease treated with gemcitabine-based chemotherapy in the first line, the 1-year survival rate achieved was 23-35%. Second-line and subsequent treatments have not consistently provided a survival benefit.

Liposomal pegylated form of the topoisomerase I inhibitor irinotecan (nal-IRI) for intravenous administration showed significant improvement in overall survival (OS) in patients with metastatic ductal carcinoma of the pancreas pre-treated with a gemcitabine regimen in the NAPOLI clinical trial when combined with 5-FU/LV. As a result of this study, the combination of nal-IRI + 5-FU/LV was approved for this indication.

Methodology of the NAPOLI Study

NAPOLI-1 was an international open-label phase III clinical trial in which patients were randomized into 3 arms:

• nal-IRI (80 mg/m² every 2 weeks) + 5-FU (2400 mg/m²) and LV (400 mg/m²) every 2 weeks (n = 117)
• nal-IRI monotherapy at a dose of 120 mg/m² every 3 weeks (n = 151)
• 5-FU (2000 mg/m²) + LV (200 mg/m²) weekly for the first 4 weeks of a 6-week cycle (n = 149)

Clinical and demographic data and therapy efficacy in the entire study population were compared with data from patients who survived at least 1 year.

Final Results

Combination therapy with nal-IRI achieved a significant OS benefit compared to 5-FU/LV therapy (6.2 vs. 4.2 months; hazard ratio [HR] 0.75; 95% confidence interval [CI] 0.57-0.99; p = 0.039). No benefit was observed with nal-IRI monotherapy (OS 4.9 months). The estimated 1-year survival rate was 26% in the nal-IRI + 5-FU/LV arm vs. 16% in the control 5-FU/LV arm.

Similar trends were observed for progression-free survival (PFS 3.1 vs. 1.5 months), objective response rate (ORR 17 vs. 1%), and disease control rate (achievement of complete or partial remission or disease stabilization: 52 vs. 24% of patients).

Safety Profile

The final results did not reveal any new safety signals compared to the preliminary analysis. The most common grade ≥ 3 adverse events in the nal-IRI + 5-FU/LV arm were neutropenia, diarrhea, vomiting, and fatigue.

Markers for Long-Term Survival

A total of 25% of patients in the nal-IRI + 5-FU/LV arm, 13% of the control group treated with 5-FU/LV, and 10% treated with nal-IRI monotherapy survived at least 1 year after starting therapy. The median OS in these groups was 23.4, 13.7, and 19.1 months, respectively.

Demographic and clinical characteristics associated with longer survival included age ≤ 65 years, Karnofsky score ≥ 90, neutrophil-to-lymphocyte ratio ≤ 5, and lower CA19-9 levels. Longer-surviving patients also had a lower incidence of liver metastases.

Conclusion

Combination therapy with nal-IRI + 5-FU/LV represents a new standard of care following gemcitabine therapy failure. This modality significantly prolongs median OS and PFS compared to 5-FU/LV treatment and has a relatively favorable safety profile with well-manageable adverse effects.

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Sources:
1. Wang-Gillam A., Hubner R. A., Siveke J. T. et al. NAPOLI-1 phase 3 study of liposomal irinotecan in metastatic pancreatic cancer: Final overall survival analysis and characteristics of long-term survivors. Eur J Cancer 2019; 108: 78-87, doi: 10.1016/j.ejca.2018.12.007.
2. SPC Onivyde. Available at: www.servier.cz/documents/SPC/Onivyde_SPC.pdf