Liposomal Irinotecan: A New Hope for The First-line Treatment of Metastatic Pancreatic Cancer

Pancreatic cancer, known as the king of cancer, was diagnosed with pancreatic ductal adenocarcinoma in approximately 496,000 people worldwide in 2020 and is the seventh leading cause of cancer-related deaths. The onset is insidious, easy to recur and metastasize, the early symptoms are not obvious, many patients are found to be at an advanced stage when they are diagnosed, and cannot be treated surgically, and most patients have metastatic lesions, resulting in extremely poor clinical treatment effect and prognosis, and the 5-year survival rate of patients (<8%)Much lower than other malignancies. With no real improvement in early detection and treatment strategies, pancreatic ductal adenocarcinoma is expected to become the second leading cause of cancer-related deaths in Western countries by 2040.

The treatment methods are nothing more than surgical resection, chemotherapy (chemotherapy), radiation therapy (radiotherapy) and interventional therapy. Among them, chemotherapy is the cornerstone of the treatment of recurrent or metastatic pancreatic cancer, but the progress of drugs is slow. The gemcitabine-based treatment regimen is currently the standard of care for the first-line treatment of pancreatic cancer, and the recent development and marketing of liposomal irinotecan provides a new option for the treatment of pancreatic cancer, and is the first drug approved by the FDA for the treatment of metastatic pancreatic cancer that has received gemcitabine-based chemotherapy regimens in the early stage, manufactured by IPSEN in the United States and SERVIER in the European market. It is the only drug that has been shown in multiple large randomized controlled trials to improve the survival of patients with advanced pancreatic ductal cancer.

Liposomal irinotecan encapsulates irinotecan in liposomes with an active lactone structure to avoid premature activation or inactivation, and 23.2% of liposomal irinotecan can still be detected in vivo 24 hours after administration, and is not converted into SN-38 or carboxylate form, liposomal irinotecan can promote the normalization of tumor blood vessels and improve the hypoxic microenvironment of tumor tissues. The global multicenter phase III clinical trial study (NAPOLI-1) investigated the efficacy of liposomal irinotecan in combination with a gemcitabine-based regimen in patients with metastatic pancreatic cancer who have progressed. The study showed that there was no significant difference in the survival advantage of the liposomal irinotecan monotherapy group compared with the 5-FU/leucovorin treatment group; However, the liposomal irinotecan and 5-FU/leucovorin group had a significant survival advantage over the 5-FU/leucovorin group, with median OS of 6.1 months and 4.2 months, median PFS of 3.1 months and 1.5 months, and ORR of 16% and 1%, respectively.

On November 9, 2022, Ipsen announced the Phase III NAPOLI 3 study of NALIRIFOX (Onivyde + 5-fluorouracil/leucovorin + oxaliplatin) for the first-line treatment of pancreatic cancer. This is a multicenter, randomized, open-label, phase III clinical trial with a total of 770 patients to evaluate the efficacy and safety of the NALIRIFOX regimen compared with nab-paclitaxel + gemcitabine in patients with previously untreated metastatic pancreatic ductal adenocarcinoma (mPDAC). NALIRIFOX is also included in the latest National Comprehensive Cancer Network as one of the recommended options for the treatment of unresectable pancreatic ductal adenocarcinoma. The clinical trial to include liposomal irinotecan in first-line treatment was the NAPOLI 3 trial, which was evaluated for safety and efficacy in an initial phase I/II trial at a dose of 70 mg/m2 for liposomal irinotecan and 60 mg/m2 for oxaliplatin. NALIRIFOX has a manageable safety profile and good activity due to myelotoxicity with subsequent MTDs determined to be liposomal irinotecan at 50 mg/m2 and oxaliplatin at 60 mg/m2, with the recommended dose of oxaliplatin for NALIRIFOX (60 mg/m2) being lower than the dose used in the FOLFIRINOX regimen (85 mg/m2). Median PFS and OS were 9.2 months (95% CI: 7.69-11.96) and 12.6 months (8.74-18.69), respectively. The NAPOLI3 trial's intention-to-treat population included 770 patients from 19 countries around the world. Approximately 31% of enrolled patients were from North America, 3% from Asia, and 66% from Eastern and Western Europe, South America, and Australia. The baseline characteristics of the two groups were very balanced, with a slightly higher proportion of patients with elevated Ca199 in the NALIFIROX group, with a median follow-up period of 16.1 months in the OS data analysis and 11.1 months (95% CI 10.0-12.1) in the NALIRIFOX group compared with a significantly higher median OS (9.2 months) in the nabitaxel plus gemcitabine group. Similarly, the median PFS was longer in the NALIFIROX group at 7.4 months, compared to the median in the naboo-paclitaxel plus gemcitabine group PFS was 5.6 months. PFS rates at 12 and 18 months were 27.4% and 13.9% and 11.4% and 3.6%, respectively, in the NALIFIROX or nabtaxel plus gemcitabine arms. THIS RESULT SUPPORTS THE NALIRIFOX REGIMEN AS A POTENTIAL NEW STANDARD OF FIRST-LINE THERAPY. In the NAPOLI3 trial, the safety profile of NALIRIFOX was manageable and consistent with the safety profile of individual therapies. Factors such as gene mutations, patient status, age, and underlying comorbidities need to be considered when deciding which of FOLFIRINOX or albumin-paclitaxel plus gemcitabine should be used as first-line therapy. The effects of drug toxicity are also considered, and two-drug combination therapy is safer than three-drug combination therapy. Liposomal irinotecan has shown significant advantages over the failure of traditional irinotecan, and has recently been approved by the U.S. and European drug agencies, and NALIRIFOX has the potential to be a new promising treatment option for patients with metastatic pancreatic ductal adenocarcinoma.