There is an urgent unmet need for more effective therapies in pancreatic cancer. The American Cancer Society estimated that approximately 49,000 new cases of pancreatic cancer will be diagnosed in the United States in 2015, and more than 40,500 people will die from this cancer.1 Pancreatic cancer is the fourth most common cause of cancer deaths in the United States.2
Survival statistics for patients with pancreatic cancer are dismal, in part because the majority of patients with pancreatic cancer are diagnosed with nonresectable advanced disease; only 4% of patients will be alive 5 years after diagnosis.2,3 Surgery and adjuvant chemotherapy with gemcitabine or 5-fluorouracil (5-FU) confers a small survival advantage, but only for patients with early-stage pancreatic cancer.3 A recent meta-analysis of patients with metastatic pancreatic cancer showed a median overall survival (OS) of 4.6 months (range, 2.8-5.7 months) from diagnosis.4
The costs associated with pancreatic cancer include significant morbidity and mortality, as well as considerable financial burden.5 A recent study analyzed the direct medical costs for pancreatic cancer using Surveillance, Epidemiology, and End Results–Medicare data from 2001 to 2007. The study included >15,000 Medicare beneficiaries aged ≥66 years with pancreatic cancer.
The mean direct medical costs were $65,500; patients with resectable locoregional disease had greater costs ($134,700) compared with unresectable or distant disease ($65,300 and $49,000, respectively).5 The popularity of targeted therapies and demographic trends are expected to affect treatment patterns and drive costs higher for patients with pancreatic cancer.5
The only potentially curative treatment for pancreatic cancer is surgical resection. However, more than 80% of patients have pancreatic cancer that is unresectable.6 Cytotoxic chemotherapy and radiation therapy are considered in the neoadjuvant and adjuvant settings, as well as for patients with unresectable disease.6
The current National Comprehensive Cancer Network guidelines for metastatic or locally advanced unresectable pancreatic cancer include several category 1 recommendations—the 4-drug combination FOLFIRINOX (leucovorin, 5-FU, irinotecan, oxaliplatin); gemcitabine plus erlotinib; gemcitabine plus albumin-bound paclitaxel; other gemcitabine-based combinations; and gemcitabine monotherapy.6 Gemcitabine monotherapy and best supportive care are appropriate options for patients with advanced pancreatic cancer and poor performance status.6
Onivyde Approved for Relapsed Pancreatic Cancer
On October 22, 2015, the US Food and Drug Administration (FDA) approved the cytotoxic agent, irinotecan liposome injection (Onivyde; Merrimack Pharmaceuticals), for use in combination with leucovorin and 5-FU, for the treatment of patients with advanced or metastatic pancreatic cancer that progressed after gemcitabine-based chemotherapy, making it the first and only FDA-approved treatment option for patients in this setting.7
The drug labeling for irinotecan liposome injection includes a boxed warning regarding the risks for severe neutropenia and severe diarrhea. The drug is not approved as a single agent for metastatic pancreatic cancer.7
The approval of irinotecan liposome injection was based on the demonstration of improved OS in the NAPOLI-1 study, a phase 3, multicenter clinical trial of 417 patients with metastatic pancreatic cancer whose disease relapsed after gemcitabine-based chemotherapy.7,8
Richard Pazdur, MD, Director of the FDA’s Office of Hematology and Oncology Products, said, “Many FDA staff who review drug applications are clinicians as well, so it’s especially rewarding when we are able to expedite access to new treatments for patients with unmet needs. By using the Priority Review designation for the application for Onivyde, patients will have earlier access to a drug that helps extend survival.”7
Mechanism of Action
Irinotecan liposome injection is a topoisomerase-1 inhibitor encapsulated in a lipid bilayer liposome. Topoisomerase-1 is an enzyme that relieves torsional strain in DNA by inducing single-strand breaks. By binding reversibly to the topoisomerase-1–DNA complex, irinotecan and its metabolite (SN-38) cause DNA damage and cell death.8
Dosage and Administration
The recommended dose of irinotecan liposome injection is 70 mg/m2 administered by intravenous (IV) infusion for 90 minutes every 2 weeks. In patients known to be homozygous for the UGT1A1*28 allele, the recommended dose is 50 mg/m2 administered by IV infusion for 90 minutes. In subsequent cycles, the dose can be increased to 70 mg/m2 as tolerated.8
Irinotecan liposome injection has no recommended dose for patients with serum bilirubin above the upper limit of normal.8
NAPOLI-1: Pivotal Phase 3 Clinical Trial
The efficacy and safety of irinotecan liposome injection were demonstrated in the NAPOLI-1 study, a multicenter, randomized, open-label, active-controlled, 3-arm clinical trial.8,9 This study enrolled 417 patients from >100 sites worldwide with metastatic pancreatic cancer and documented disease progression after gemcitabine-based therapy.7-9 Study inclusion criteria included serum bilirubin levels within the institutional normal range, albumin levels ≥3 g/dL, and Karnofsky Performance Status (KPS) ≥70.8
Patients in the NAPOLI-1 clinical trial were randomized to 1 of 3 of the following regimens until disease progression or until unacceptable toxicity8:
- Irinotecan liposome injection, leucovorin, and 5-FU (ILF): irinotecan liposome injection 70 mg/m2 for 90 minutes, leucovorin 400 mg/m2 for 30 minutes, and 5-FU 2400 mg/m2 for 46 hours every 2 weeks
- Irinotecan liposome injection 100 mg/m2 for 90 minutes every 3 weeks
- Leucovorin and 5-FU (control arm): leucovorin 200 mg/m2 and 5-FU 2000 mg/m2 for 24 hours weekly for 4 weeks with a 2-week rest.
Patients in the first 2 arms who were homozygous for the UGT1A1*28 allele started treatment with irinotecan liposome injection at a reduced dose.7,8
The primary end point of this study was OS. Each irinotecan liposome injection–containing arm was compared with the control arm—5-FU plus leucovorin. The secondary end points were progression-free survival (PFS) and overall response rate (ORR). The tumor status assessments were performed at baseline, then every 6 weeks.8
NAPOLI-1 was initiated as a 2-arm study and amended after initiation to include the third arm—irinotecan liposome injection plus leucovorin and 5-FU. Comparisons between the ILF regimen and the control arm are limited to patients who were enrolled in the trial after this amendment.8
Overall, 236 patients were randomized to the ILF regimen (N = 117) or to the control arm (N = 119) after the addition of the third arm of the study. The patients’ median age was 63 years (range, 34-81 years); the mean baseline albumin levels were 3.97 g/dL; and 53% of patients had a KPS of 90 to 100. The patients’ disease characteristics included liver metastasis (67%) and lung metastasis (31%).8
All patients previously received gemcitabine, either alone or in combination. Overall, 13% of patients received gemcitabine combined with albumin-bound paclitaxel.8
The OS analysis demonstrated a significant benefit for patients receiving the ILF regimen. In the intention-to-treat population, the median OS was 6.1 months (95% confidence interval [CI], 4.8-8.5) for the irinotecan liposome injection–based combination compared with 4.2 months (95% CI, 3.3-5.3) for the control arm (hazard ratio [HR] for death, 0.68; 95% CI, 0.50-0.93; P = .014). The OS was not improved when irinotecan liposome injection monotherapy was compared with the control arm (HR, 1.00; P = .97).8
In addition, the PFS and ORR were significantly improved in the ILF group compared with the control group. The median PFS was 3.1 months in patients with pancreatic cancer receiving the ILF combination (95% CI, 2.7-4.2) versus 1.5 months for the control arm (95% CI, 1.4-1.8; HR, 0.55). According to an independent review, the ORR was also improved with ILF compared with the control arm (Table).8
The safety of irinotecan liposome injection was established based on results of the NAPOLI-1 clinical trial.9 The median duration of exposure was 9 weeks in both irinotecan liposome injection–containing arms compared with 6 weeks in the control arm.7,8
The most frequently reported nonhematologic adverse reactions associated with irinotecan liposome injection included diarrhea, fatigue, vomiting, nausea, anorexia, stomatitis, and fever.7 The most common (≥2%) serious adverse reactions were diarrhea, vomiting, neutropenic fever or neutropenic sepsis, nausea, pyrexia, sepsis, dehydration, septic shock, pneumonia, acute renal failure, and thrombocytopenia.8
Among patients who received ILF in the NAPOLI-1 study, grade 3 or 4 hematologic adverse reactions included lymphopenia (27%), neutropenia (20%), anemia (6%), and thrombocytopenia (2%). Grade 3 or 4 elevations in alanine aminotransferase levels were reported in 6% of patients receiving ILF.8
Adverse reactions requiring permanent discontinuation of irinotecan liposome injection occurred in 11% of patients receiving the ILF regimen and included diarrhea, vomiting, and sepsis. Overall, 33% of patients receiving ILF required dose reductions of irinotecan liposome injection because of adverse reactions, which included neutropenia, diarrhea, nausea, and anemia. Irinotecan liposome injection was held or delayed because of adverse reactions (ie, neutropenia, diarrhea, fatigue, vomiting, and thrombocytopenia) in 62% of patients receiving ILF.8
The concomitant use of irinotecan liposome injection with strong inducers of the cytochrome (CY) P3A4 enzyme, such as phenytoin and rifampin, should be avoided.8
The use of irinotecan liposome injection with other inhibitors of CYP3A4 or UGT1A1 can increase systemic exposure to irinotecan or SN-38. The use of strong CYP3A4 or UGT1A1 inhibitors should be avoided, if possible. These agents should be discontinued at least 1 week before starting therapy with irinotecan liposome injection.8
Irinotecan liposome injection is contraindicated in patients who had a severe hypersensitivity reaction to this medication or to irinotecan hydrochloride.8
Warnings and Precautions
Boxed warning. The prescribing information for irinotecan liposome injection contains a boxed warning stating that treatment with irinotecan liposome injection is associated with severe neutropenia and severe diarrhea.8
Severe neutropenia. Irinotecan liposome injection can cause life-threatening neutropenia and fatal neutropenic sepsis. These complications were more common in Asian patients in the NAPOLI-1 study.8
Complete blood cell counts should be performed on days 1 and 8 of every cycle or more frequently, if clinically indicated. Irinotecan liposome injection should be withheld if the absolute neutrophil count (ANC) falls below 1500/mm3 or if neutropenic fever occurs. It can be resumed when the ANC is at least 1500/mm3. After recovery from grade 3 or 4 neutropenia or neutropenic fever, subsequent doses should be reduced.8
Severe diarrhea. Life-threatening diarrhea can occur with irinotecan liposome injection therapy. This agent should not be administered to patients with bowel obstruction.
Early-onset diarrhea sometimes occurred with other symptoms of a cholinergic reaction. An individual patient can experience early- and late-onset diarrhea.8
Irinotecan liposome injection should be withheld for grade 2, 3, or 4 diarrhea, and loperamide should be administered for late-onset diarrhea of any severity. For early-onset diarrhea of any severity, IV or subcutaneous atropine should be administered (unless it is contraindicated). After recovery to grade 1 diarrhea, irinotecan liposome injection can be resumed at a lower dose.8
Interstitial lung disease. Irinotecan can cause severe and fatal interstitial lung disease. The drug should be withheld in patients with new or progressive dyspnea, cough, and fever. It should be discontinued in patients whose diagnosis of interstitial lung disease is confirmed.8
Severe hypersensitivity reaction. Patients with severe hypersensitivity reaction to irinotecan liposome injection should permanently discontinue its use.8
Embryofetal toxicity. Irinotecan liposome injection can cause fetal harm. Pregnant women should be advised of this risk.8
Use in Specific Populations
Pediatric patients. The safety and efficacy of irinotecan liposome injection have not been established in children.8
Geriatric use. No overall differences in efficacy or safety of irinotecan liposome injection were observed between older (aged ≥65 years) and younger patients.8
Pregnancy. Pregnant women should be advised that irinotecan liposome injection can cause fetal harm.8
Nursing mothers. It is not known whether irinotecan liposome injection is excreted in human milk. Nursing should be discontinued during irinotecan liposome injection therapy and for 1 month after the last dose.8
Men and women of reproductive potential. Women of childbearing potential should use effective contraception during treatment with irinotecan liposome injection and for 1 month after the final dose.8 Males should use condoms during treatment with irinotecan liposome injection and for 4 months after the final dose.8
Renal impairment. Mild and moderate renal impairment had no effect on irinotecan liposome injection or on SN-38 levels. Irinotecan liposome injection has not been studied in patients with severe renal impairment.8
Hepatic impairment. Irinotecan liposome injection has not been studied in patients with hepatic impairment.8
The FDA approval of irinotecan liposome injection has added a new treatment option for patients with pancreatic cancer. The drug is only approved for use in combination with leucovorin and 5-FU. This combination is the first FDA-approved treatment option for patients with metastatic pancreatic cancer that has relapsed after a gemcitabine-containing regimen. This combination offers a significant survival benefit, with an acceptable tolerability profile. Additional studies of irinotecan liposome injection in pancreatic cancer are currently under way, as well as in adults with recurrent, high-grade glioma, and in children with solid tumors.10
1. American Cancer Society. What are the key statistics about pancreatic cancer? Revised January 9, 2015. www.cancer.org/cancer/pancreaticcancer/detailedguide/pancreatic-cancer-key-statistics. Accessed October 29, 2015.
2. Siegel RL, Miller KD, Jemal A. Cancer statistics, 2015. CA Cancer J Clin. 2015;65:5-29.
3. American Cancer Society. Pancreatic cancer survival by stage. Revised January 9, 2015. www.cancer.org/cancer/pancreaticcancer/detailedguide/pancreatic-cancer-survival-rates. Accessed October 29, 2015.
4. Carrato A, Falcone A, Ducreux M, et al. A systematic review of the burden of pancreatic cancer in Europe: real-world impact on survival, quality of life and costs. J Gastrointest Cancer. 2015;46:201-211.
5. O’Neill CB, Atoria CL, O’Reilly EM, et al. Costs and trends in pancreatic cancer treatment. Cancer. 2012;118:5132-5139.
6. National Comprehensive Cancer Network. NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines): pancreatic adenocarcinoma. Version 2.2015. March 6, 2015. www.nccn.org/professionals/physician_gls/pdf/pancreatic.pdf. Accessed October 29, 2015.
7. US Food and Drug Administration. FDA approves new treatment for advanced pancreatic cancer. Press release. October 22, 2015. www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm468654.htm. Accessed October 29, 2015.
8. Onivyde (irinotecan liposome injection) [prescribing information]. Cambridge, MA: Merrimack Pharmaceuticals, Inc; October 2015.
9. Wang-Gillam A, Li CP, Bodoky G, et al; for the NAPOLI-1 Study Group. Nanoliposomal irinotecan with fluorouracil and folinic acid in metastatic pancreatic cancer after previous gemcitabine-based therapy (NAPOLI-1): a global, randomised, open-label, phase 3 trial. Lancet. 2015 Nov 29. Epub ahead of print.
10. ClinicalTrials.gov. MM-398. Search results. https://clinicaltrials.gov/ct2/results?term=MM-398&Search= Search. Accessed November 9, 2015.