Coverage Policy Manual
Policy #: 2021018
Category: Pharmacy
Initiated: June 2021
Last Review: April 2024
  Irinotecan Liposomal (e.g., Onivyde)
Description:
Irinotecan liposomal is a topoisomerase inhibitor. Topoisomerase is an enzyme in cells that helps with the transcription and replication of DNA. Topoisomerases break and rejoin DNA strands during cell replication. Cells need this enzyme to keep their DNA in the proper shape when they are dividing. Blocking this enzyme leads to a permanent breakage in the DNA, which leads to cell death. Irinotecan Liposomal is indicated in combination with fluorouracil and leucovorin, for the treatment of individuals  with metastatic adenocarcinoma of the pancreas after disease progression following gemcitabine-based therapy (Onivyde, 2015).
 
The most common type of pancreatic malignancy is pancreatic ductal adenocarcinoma (PDAC). It accounts for more than 90% of all cases. PDAC is highly lethal as it is aggressive and is usually diagnosed at a later stage due to lack of early symptoms. In addition, it is resistant to many conventional cytotoxic and targeted anticancer agents. 20-30% of individuals  with PDAC are diagnosed with locally-advanced, unresectable disease and 50-55% are diagnosed with metastatic disease. There are limited treatment options, and most are systemic chemotherapy of palliative intent. Therefore, despite some significant advances in the management of PDAC over the past decade, it continues to have a poor prognosis with a 5-year survival rate of 8–11%. Irinotecan liposomal in combination with fluorouracil and leucovorin was the first regimen specifically approved for use as a second- or subsequent-line therapy in gemcitabine-treated individuals  with metastatic PDAC and is a valuable treatment option in this situation (Frampton, 2020).
 
Irinotecan liposomal carries a black box warning for neutropenic sepsis and severe diarrhea. Life-threatening neutropenia and fatal neutropenic sepsis can occur. Complete blood cell counts should be monitored on days 1 and 8 of every cycle and more frequently if clinically indicated. Irinotecan liposomal should not be administered in individuals with neutrophil counts of < 1,500 cells/mm3 or in individuals with neutropenic fever. Additionally, irinotecan liposomal can cause severe and life-threatening diarrhea. Dose should be held for individuals experiencing diarrhea of Grade 2-4 severity. Loperamide should be administered for late diarrhea of any severity, and atropine, if not contraindicated, should be administered for early diarrhea of any severity. Further, irinotecan liposomal should not be administered to individuals with bowel obstruction. Warnings and precautions are also given for interstitial disease, severe hypersensitivity reaction, and embryo-fetal toxicity (Onivyde, 2015).
 
Regulatory Status
 
Irinotecan Liposomal (e.g., Onivyde) was approved by the U.S. Food and Drug Administration (FDA) on October 22, 2015 for the treatment of post-gemcitabine metastatic adenocarcinoma of the pancreas.
 
On February 13, 2024, the U.S. Food and Drug Administration approved Irinotecan liposomal in combination with oxaliplatin, fluorouracil and leucovorin, for the first-line treatment of adult individuals with metastatic pancreatic adenocarcinoma.
 
Coding
 
See CPT/HCPCS Code section below
Policy/
Coverage:
Prior Approval is required for Irinotecan Liposomal (e.g., Onivyde).   
 
The Step Therapy Medication Act is applicable to fully insured (Arkansas Blue Cross, Health Advantage, and Exchange) and specified governmental (ASE/PSE and ASP) health plans. The law is not applicable to FEP or self-insured ERISA groups (including but not limited to Walmart or other Blue Advantage groups). Initial approval for exigent request is 28 days. Otherwise, initial approval for standard review is up to 1 year.
 
Effective August 1, 2021, for members of plans that utilize an oncology benefits management program, Prior Approval is required for this service and is managed through the oncology benefits management program.
 
Effective April 17, 2024
 
Meets Primary Coverage Criteria Or Is Covered For Contracts Without Primary Coverage Criteria
 
Irinotecan liposomal (e.g., Onivyde)meets member benefit certificate primary coverage criteria that there be scientific evidence in improving health outcomes when ALL the following criteria are met:
 
FDA Labeled Indications
 
For FDA labeled indications, all products must be dosed in accordance with the FDA label unless otherwise specified.
 
STANDARD REVIEW for up to 12 months:
 
1. Individual has a diagnosis of metastatic pancreatic adenocarcinoma (Onivyde, 2024); AND
2. Individual is 18 years of age or older (Onivyde, 2024); AND
3. Individual does not have a bowel obstruction (Onivyde, 2024); AND
4 Individual has not previously received conventional irinotecan therapy (NCCN 1); AND
5. Individual has an ECOG* performance status of 0-2 (see policy guidelines); AND
6. In a first-line treatment setting, Must be used in combination with oxaliplatin, fluorouracil and leucovorin (Onivyde, 2024); OR
7. After disease progression following gemcitabine-based therapy, must be used in combination with fluorouracil and leucovorin (Onivyde, 2024; Wang-Gillam, 2019; NCCN 1).
 
Off-Label Indications
 
For  off-label indications, authorizations will not exceed 50 mg/square meters intravenous infusion every two weeks for irinotecan in combination with oxaliplatin, fluorouracil and leucovorin or 70 mg/square meters intravenous infusion every two weeks for irinotecan in combination with fluorouracil and leucovorin unless medical literature supports a higher dose.
 
STANDARD REVIEW for up to 12 months:
 
1. Individual has a diagnosis of Ampullary Adenocarcinoma:
a. Therapy for disease progression in individuals with good performance status (ECOG 0-1, with good biliary drainage and adequate nutritional intake) and pancreatobiliary and mixed type in combination with fluorouracil and leucovorin if previously treated with prior:
i. Gemcitabine-based therapy (NCCN 2A); OR
ii. Fluoropyrimidine-based therapy if no prior irinotecan (NCCN 2A); OR
iii. Oxaliplatin-based therapy (e.g., capecitabine, 5-fluorouracil) if no prior irinotecan(NCCN 2A); OR
2. Individual has a diagnosis of Pancreatic Adenocarcinoma:
a. Induction therapy followed by chemoradiation for locally advanced disease and good performance status (defined as ECOG PS 0-1, with good biliary drainage and adequate nutritional intake) as a component of fluorouracil, leucovorin, liposomal irinotecan, and oxaliplatin (NALIRIFOX) protocol. (NCCN 2A); OR
b. Subsequent therapy in combination with leucovorin and fluorouracil for locally advanced or metastatic disease and disease progression if good performance status (defined as ECOG PS 0-1, with good biliary drainage and adequate nutritional intake) or intermediate PS (ECOG PS 2) and previously treated with fluoropyrimidine-based therapy (e.g., capecitabine, 5-fluorouracil) and no prior irinotecan (NCCN 2A); OR
c. Therapy if good performance status (ECOG PS 0-1) or intermediate PS (ECOG PS 2) in combination with fluorouracil and leucovorin:
i. With (if not previously done) or without chemoradiation for local recurrence in the pancreatic operative bed after resection; OR
ii. For recurrent metastatic disease with or without local recurrence after resection; AND
iii. The above regimen is used if:
1. Less than 6 months from completion of primary therapy and previously treated with gemcitabine-based therapy (NCCN 1); OR
2. Less than 6 months from completion of primary therapy and previously treated with fluoropyrimidine-based therapy that did not include irinotecan (NCCN 2A); OR
3. Greater than or equal to 6 months from completion of primary therapy as alternate systemic therapy not previously used (NCCN 2A).
 
Limitations of Use: Irinotecan Liposomal is not indicated as a single agent for the treatment of individuals with metastatic pancreatic adenocarcinoma. (Onivyde, 2024)
 
Policy Guidelines
 
*Eastern Cooperative Oncology Group (ECOG) Performance scale:
    • 0 = Fully active, able to carry on all pre-disease performance without restriction
    • 1 = Restricted in physically strenuous activity but ambulatory and able to carry out work of a light or sedentary nature, for example, light housework, office work
    • 2 = Ambulatory and capable of all self-care but unable to carry out any work activities. Up and about more than 50% of waking hours
    • 3 = Capable of only limited self-care, confined to bed or chair more than 50% of waking hours
    • 4 = Completely disabled. Cannot carry on any self-care. Totally confined to bed or chair
    • 5 = Dead
 
The use of this drug is covered if an FDA-approved oncologic indication exists (not listed as an indication above) with the member meeting all the additional requirements of the prescribing information (package insert listed in the “Indications and Usage”) AND/OR a NCCN category 1 or 2A recommendation is recognized in the NCCN Drugs and Biologics Compendium with the member meeting all specified criteria (see policy #2000030).
 
Dosage and Administration
 
Irinotecan liposomal in combination with oxaliplatin, fluorouracil and leucovorin:
    • The recommended dose is 50 mg/square meters intravenous infusion over 90 minutes every two weeks.
    • The recommended starting dose in individual homozygous for UGR1A1*28 is 50 mg/square meters every two weeks.
 
Ironetecan liposomal in combination with fluorouracil and leucovorin
    • The recommended dose is 70 mg/square meters intravenous infusion over 90 minutes every two weeks.
    • The recommended starting dose in individuals homozygous for UGT1A1*28 is 50 mg/square meters every two weeks.  
 
Irinotecan Liposomal is available as 43 mg/10 mL in a single dose vial.
 
Please refer to a separate policy on Site of Care or Site of Service Review policy #2018030 for pharmacologic/biologic medications.
 
Does Not Meet Primary Coverage Criteria Or Is Investigational For Contracts Without Primary Coverage Criteria
 
Irinotecan liposomal (e.g., Onivyde) for any indication or circumstance not described above, does not meet member benefit certificate primary coverage criteria that there be scientific evidence of effectiveness in improving health outcomes.
 
For members with contracts without primary coverage criteria, Irinotecan liposomal for any indication or circumstance not described above is considered investigational. Investigational services are specific contract exclusions in most member benefit certificates of coverage.
 
Effective January 2022 to April 16, 2024
 
Meets Primary Coverage Criteria Or Is Covered For Contracts Without Primary Coverage Criteria
 
The use of Irinotecan liposomal meets member benefit certificate primary coverage criteria that there be scientific evidence in improving health outcomes for the treatment of individuals with locally advanced or metastatic pancreatic adenocarcinoma when ALL the following criteria for one of the following are met:
 
Locally advanced or metastatic pancreatic adenocarcinoma:
1. Individual does not have bowel obstruction (FDA, Onivyde, 2015) AND
2. Individual is 18 years of age or (FDA, Onivyde, 2015) AND
3. Individual has not previously received conventional irinotecan therapy (NCCN 1, NCCN v.2.2021) AND
4. Individual has *ECOG performance 0-2 (NCCN v.2.2021) AND
5. Must be used in combination with fluorouracil and leucovorin (FDA, Onivyde, 2015) AND
6. Following previous treatment with one of the following:
a. Gemcitabine-based therapy (NCCN 1, NCCN v.2.2021; Wang-Gillam, 2019); OR
b. Fluoropyrimidine-based therapy (NCCN 2A, NCCN v.2.2021); AND
7. Must be dosed in accordance with the FDA label.
 
Local recurrence of pancreatic adenocarcinoma in the pancreatic operative bed post resection (NCCN 2A):
1. Individual is 18 years of age or older (Onivyde FDA Label, 2015); AND
2. Individual has not previously received conventional irinotecan therapy (NCCN 1, NCCN v.2.2021); AND
3. Individual has *ECOG performance 0-2 (NCCN v.2.2021); AND
4. Used in combination with fluorouracil and leucovorin (Onivyde FDA Label, 2015) with or without radiation therapy; AND
5. One of the following conditions exist:
a. If less than 6 months from completion of primary therapy and previously treated with gemcitabine-based therapy (NCCN 2A, NCCN v.2.2021); OR
b. If less than 6 months from completion of primary therapy and previously treated with fluoropyrimidine-based therapy that did not include irinotecan (NCCN 1, NCCN v.2.2021); OR
c. If ≥ 6 months from completion of primary therapy (NCCN 1, NCCN v.2.2021); AND
6. Must be dosed in accordance with the FDA label.
 
Adjuvant therapy in recurrent metastatic disease with or without local recurrence after resection when all the below are met (NCCN 2A):
1. Individual is 18 years of age or older (Onivyde FDA Label, 2015); AND
2. Individual has not previously received conventional irinotecan therapy (NCCN 1, NCCN v.2.2021); AND
3. Individual has *ECOG performance 0-2 (NCCN v.2.2021); AND
4. Used in combination with fluorouracil and leucovorin (Onivyde FDA Label, 2015); AND
5. One of the following conditions exist:
a. If less than 6 months from completion of primary therapy and previously treated with gemcitabine-based therapy (NCCN 1, NCCN v.2.2021); OR
b. If less than 6 months from completion of primary therapy and previously treated with fluoropyrimidine-based therapy that did not include irinotecan (NCCN 1, NCCN v.2.2021); OR
c. If ≥ 6 months from completion of primary therapy (NCCN 1, NCCN v.2.2021); AND
6. Must be dosed in accordance with the FDA label.
 
*Eastern Cooperative Oncology Group (ECOG) Performance scale:
    • 0 = Fully active, able to carry on all pre-disease performance without restriction
    • 1 = Restricted in physically strenuous activity but ambulatory and able to carry out work of a light or sedentary nature, for example, light housework, office work
    • 2 = Ambulatory and capable of all self-care but unable to carry out any work activities. Up and about more than 50% of waking hours
    • 3 = Capable of only limited self-care, confined to bed or chair more than 50% of waking hours
    • 4 = Completely disabled. Cannot carry on any self-care. Totally confined to bed or chair
    • 5 = Dead
 
The use of this drug is covered if an FDA-approved oncologic indication exists (not listed as an indication above) with the member meeting all the additional requirements of the prescribing information (package insert listed in the “Indications and Usage”) AND/OR a NCCN category 1 or 2A recommendation is recognized in the NCCN Drugs and Biologics Compendium with the member meeting all specified criteria (see policy #2000030).
 
Dosage and Administration
Dosing per FDA Guidelines
 
Note: Refer to the Prescribing Information for more complete dosing information.
 
Recommended dose of Irinotecan Liposomal is 70 mg/square meters intravenous infusion over 90 minutes every two weeks.
 
Recommended starting dose of Irinotecan Liposomal in individuals homozygous for UGT1A1*28 is 50 mg/square meters every two weeks.
 
Irinotecan Liposomal is available as 43 mg/10 mL in a single dose vial.
 
Please refer to a separate policy on Site of Care or Site of Service Review policy #2018030 for pharmacologic/biologic medications.
 
Does Not Meet Primary Coverage Criteria Or Is Investigational For Contracts Without Primary Coverage Criteria
 
The use of Irinotecan liposomal for any indication or circumstance other than those listed above, does not meet member benefit certificate primary coverage criteria that there be scientific evidence of effectiveness in improving health outcomes.
 
Use: Irinotecan liposome injection is not indicated as a single agent for the treatment of individuals with metastatic adenocarcinoma of the pancreas (NCCN v2.2021).
 
For members with contracts without primary coverage criteria, the use of Irinotecan liposomal for any indication or circumstance other than those listed above is considered investigational.  Investigational services are specific contract exclusions in most member benefit certificates of coverage.
 
Effective June 1, 2021 to January 2022
 
Meets Primary Coverage Criteria Or Is Covered For Contracts Without Primary Coverage Criteria
 
The use of Irinotecan liposomal (Onivyde) for the treatment of individuals with locally advanced or metastatic pancreatic adenocarcinoma meets member benefit certificate primary coverage criteria when ALL of the following criteria are met:
 
    • Individual does not have bowel obstruction AND
    • Individual is 18 years of age or older AND
    • Individual has not previously received conventional irinotecan therapy AND
    • Individual has *ECOG performance 0-2 AND
    • Must be used in combination with fluorouracil and leucovorin AND
    • Following previous treatment with one of the following:
        • Gemcitabine-based therapy OR
        • Fluoropyrimidine -based therapy
 
*Eastern Cooperative Oncology Group (ECOG) Performance scale:
 
0 = Fully active, able to carry on all pre-disease performance without restriction
1 = Restricted in physically strenuous activity but ambulatory and able to carry out work of a light or sedentary nature, for example, light house work, office work
2 = Ambulatory and capable of all self-care but unable to carry out any work activities. Up and about more than 50% of waking hours
3 = Capable of only limited self-care, confined to bed or chair more than 50% of waking hours
4 = Completely disabled. Cannot carry on any self-care. Totally confined to bed or chair
5 = Dead
 
The use of this drug is covered if a FDA-approved oncologic indication exists (not listed as an indication above) with the member meeting all of the additional requirements of the prescribing information (package insert listed in the “Indications and Usage”) AND/OR a NCCN category 1 or 2A recommendation is recognized in the NCCN Drugs and Biologics Compendium with the member meeting all of specified criteria (see policy #2000030).
 
Dosage and Administration
 
Note: Refer to the Prescribing Information for more complete dosing information.
 
    • Recommended dose of ONIVYDE is 70 mg/m2 intravenous infusion over 90 minutes every two weeks.
    • Recommended starting dose of ONIVYDE in patients homozygous for UGT1A1*28 is 50 mg/m2 every two weeks.
 
Please refer to a separate policy on Site of Care or Site of Service Review policy #2018030 for pharmacologic/biologic medications.
 
Does Not Meet Primary Coverage Criteria Or Is Investigational For Contracts Without Primary Coverage Criteria
 
The use of Irinotecan liposomal (Onivyde) does not meet member benefit certificate primary coverage criteria for any indication not listed above.
 
For members with contracts without primary coverage criteria, the use of Irinotecan liposomal (Onivyde) for any indication not listed above is considered investigational.  Investigational services are specific contract exclusions in most member benefit certificates of coverage.
Rationale:
Liposomal irinotecan is an intravenously administered, liposomal encapsulated formulation of irinotecan that was developed with the aim of maximizing anti-tumor efficacy while minimizing drug-related toxicities (Frampton, 2020). The liposomal formulation prevents early metabolism keeping the medication in plasma circulation and in tissues longer resulting in increased active drug delivery to the tumor. Irinotecan works by inhibiting topoisomerase activity in tumors, and subsequently halting rapid cell division. (Woo, 2019)
 
Patients who are diagnosed with pancreatic cancer generally have a poor prognosis. A phase II trial of patients diagnosed with pancreatic ductal adenocarcinoma (PDAC) showed that liposomal irinotecan (Nal-IRI) produced median overall and median progression-free survival rates of 5.2 and 2.4 months, respectively. These findings led to a large randomized, phase III clinical trial called NAPOLI-1. This study involved 417 patients at 76 sites in 14 countries (Woo, 2019). Liposomal irinotecan (Nal-IRI), in combination with 5-fluorouracil and leucovorin (5-FU/LV), was found to significantly improve survival in patients who progressed on gemcitabine-based therapy in the NAPOLI-1 trial (Wang-Gillam, 2019). Patients with metastatic PDAC who were treated with Nal-IRI in combination with 5-FU and LV following gemcitabine-based therapy had improved overall survival (OS), progression-free survival (PFS), objective response rate, and CA19-9 response versus those treated with 5-FU/LV alone according to the results of the phase 3 NAPOLI-1 trial (NCT01494506) (Wang-Gillam, 2019). Median overall survival was 6.1 months in patients treated with Nal-IRI in combination with5-FU/LV versus 4.2 months in those treated with 5-FU/LV alone. Overall response rate was 16% in patients treated with Nal-IRI in combination with5-FU/LV versus 1% in those treated with 5-FU/LV alone. CA 19-9 response rates were 29% (28/97) in patients treated with Nal-IRI in combination with5-FU/LV versus 9% (7/81) in those treated with 5-FU/LV alone. The results of this study led to the FDA approval of Nal-IRI in combination with 5-FU/LV, for the treatment of patients with metastatic adenocarcinoma of the pancreas after disease progression following gemcitabine-based therapy.
 
In the NAPOLI-1 trial, Nal-IRI in combination with5-FU/LV demonstrated improved overall survival in patients with metastatic pancreatic cancer compared to those on 5-FU/LV therapy alone.  However, no trials comparing Nal-IRI in combination with5-FU/LV with FOLRIRI were done. From October 2015 to August 2018, a single-center, retrospective, cohort study of patients between the ages of 18-89 with locally advanced or metastatic pancreatic cancer comparing Nal-IRI in combination with 5-FU/LV versus FOLRIRI was conducted. The purpose of the trial was to determine if Nal-IRI in combination with 5-FU/LV and FOLFIRI are similarly effective for the treatment of advanced pancreatic cancer. 35 participants received Nal-IRI in combination with 5-FU/LV and 40 received FOLFIRI. Nearly all the patients (88%) in the study had metastatic disease This single-center retrospective study showed that both Nal-IRI in combination with 5-FU/LV and FOLFIRI treatment lead to similar survival outcomes in patients with advanced pancreatic cancer. Both median progressive-free survival and overall survival were similar between the two groups. The observed progressive-free survival was 4.1 months for the Nal-IRI in combination with 5-FU/LV group, and 3.1 months in the FOLFIRI group. These results are in line with outcomes of previous trial reports. Several limitations merit consideration with regard to this study. This study was a retrospective analysis so there are limitations inherent to the design including the reliance on accurate documentation for the reporting of adverse effects. In addition, there is a possibility of treatment selection bias, and the small sample size was small. However, this study found similar survival and toxicity outcomes for advanced pancreatic cancer patients treated with either Nal-IRI in combination with 5-FU/LV or FOLFIRI. Future trials are needed to confirm the results of this study (Tossey, 2019).
 
Nal-IRI in combination with 5-FU/LV was approved by the FDA as a subsequent treatment following gemcitabine-based therapy in patients with metastatic disease. NCCN recommends this regimen as a subsequent treatment option for patients with good performance status and disease progression (NCCN, 2021). The American Society of Clinical Oncology (ASCO) guideline on the management of metastatic PDAC states that Nal-IRI in combination with 5-FU/LV is preferred as second-line therapy for patients with first-line treatment with gemcitabine + nab-paclitaxel, an ECOG PS of 0–1 and a relatively favorable comorbidity profile. Similarly, the National Comprehensive Cancer Network (NCCN) guideline includes a category 1 recommendation (i.e. based upon high-level evidence and uniform consensus) for the use of Nal-IRI + 5-FU/LV as a second-line option in patients with metastatic PDAC previously treated with gemcitabine-based therapy and good PS. Additionally, an update to the European Society for Medical Oncology (ESMO) guideline states Nal-IRI + 5-FU/LV may constitute an active and tolerable second-line treatment option for fit patients with metastatic PDAC previously treated with gemcitabine-based therapy (Frampton, 2020).
 
In addition, NCCN recommends Nal-IRI in combination with 5-FU/LV for locally advanced disease following treatment with gemcitabine-based therapy (NCCN, 2021). Also, NCCN recommends treatment with Nal-IRI in combination with 5-FU/LV for patients with locally advanced or metastatic pancreatic cancer with good performance status who were previously treated with fluoropyrimidine-based therapy. Finally, NCCN recommends therapy with (if not previously done) or without chemoradiation in combination with 5-FU/LV for local recurrence in the pancreatic operative bed after resection or metastatic disease with or without local recurrence after resection if ≥ 6 months from completion of primary therapy in patients with good performance status (ECOG PS 0-2) (NCCN, 2021). Treatment for metastatic disease following gemcitabine-based therapy is a NCCN 1 recommendation. The other NCCN recommendations for irinotecan liposome for pancreatic cancer are NCCN 2A recommendations.
 
Results of the NAPOLI-1 trial led to approval of Nal-IRI in combination with 5-FU/LV for the treatment of metastatic PDAC after gemcitabine-based therapy for patients whose disease progressed on gemcitabine- based therapy and whose ECOG (Eastern Cooperative Oncology Group) status was 0-2 (Mercade, 2020). The NAPOLI-1 only included a few patients who were previously treated with irinotecan. Therefore, the efficacy of Nal-IRI after FOLFIRINOX was not clear. Glassman et al conducted a study with 56 patients with advanced PDAC who received Nal-IRI +5-FU/LV. The median OS and PFS were 5.3 and 2.9 months, respectively. However, patients who progressed previously on irinotecan-based chemotherapy experienced worse outcomes on Nal-IRI compared to those who were irinotecan naïve. Patients with prior irinotecan had a median OS of 3.9 months, compared to 7.7 months in irinotecan naïve patients. PFS was also worse in patients with prior irinotecan, with PFS falling from 5.7 to 2.2 months (Woo, 2019).
 
In NAPOLI-1, key inclusion criteria were good performance status and adequate hematological (absolute neutrophil counts >1.5×10 cells/L), hepatic (normal total bilirubin, and albumin levels ≥30 g/L), and renal function. It was determined that it might be prudent not to offer systemic therapy in patients with poor performance status since they were excluded from the study (Woo, 2019).
 
A number of clinical trials for Na1-IRI are underway. The FUNGE-MAX and FOOTPATH trials are examining the efficacy of Nal-IRI /5-FU/LV compared to gemcitabine and nab-paclitaxel as first-line therapy. Other trials include replacing traditional irinotecan with Nal-IRI as part of neoadjuvant FOLFIRINOX for patients who may undergo resection of pancreatic cancer; comparing Nal-IRI with cabiralizumab and nivolumab immunotherapy and combinations of immunotherapy plus traditional chemotherapy; and assessing the safety and efficacy of Nal-IRI plus other therapies in previously untreated PDAC (Woo, 2019).
 
2022 Update
Annual policy review completed with a literature search using the MEDLINE database through April 2022. No new literature was identified that would prompt a change in the coverage statement.
 
2023 Update
Annual policy review completed with a literature search using the MEDLINE database through April 2023. No new literature was identified that would prompt a change in the coverage statement.
 
2024 Update
The efficacy of ONIVYDE in combination with oxaliplatin, fluorouracil and leucovorin (NALIRIFOX) was evaluated in NAPOLI 3 (NCT04083235), a randomized, multicenter, open label, active-controlled trial in 770 patients with metastatic pancreatic adenocarcinoma who had not previously received chemotherapy in the metastatic setting. Randomization was stratified by region, liver metastases and ECOG performance status. Patients were randomized (1:1) to receive one of the following treatment arm:
 
    • NALIRIFOX: ONIVYDE 50 mg/m2 as an intravenous infusion over 90 minutes, followed by oxaliplatin 60 mg/m2 as an intravenous infusion over 120 minutes, followed by leucovorin 400 mg/m2 intravenously over 30 minutes, followed by fluorouracil 2400 mg/m2 intravenously over 46 hours, every 2 weeks.
    • Gem+NabP: Nab-paclitaxel 125 mg/m2 as an intravenous infusion over 35 minutes, followed by gemcitabine 1000 mg/m2 intravenously over 30 minutes on days 1, 8 and 15 of each 28-day cycle.
 
Patients homozygous for the UGT1A1*28 allele initiated ONIVYDE at the same dose (50 mg/m2 ONIVYDE). Treatment continued until RECIST v1.1 defined disease progression or unacceptable toxicity. Tumor status assessments were conducted at baseline and every 8 weeks thereafter as assessed by the investigator according to RECIST v1.1. The main efficacy outcome measure was overall survival (OS). Additional efficacy measures were investigator-assessed progression-free survival (PFS) and objective response rate (ORR).
 
Baseline demographic and patient characteristics were: median age of 65 years (range: 20-85); 50% age 65 or older; 56% male; 83% White, 4.9% Asian, 2.5% Black or African American, 0.4% multiple race, 0.3% American Indian or Alaska Native; 0.1% Native Hawaiian or other Pacific Islander, 1.7% other, 7% not reported; and 82% non-Hispanic, 10% Hispanic, 8% not reported. ECOG performance status was 0 or 1 in 44% and 56% of patients, respectively; 80% had liver metastases.
 
NAPOLI 3 demonstrated a statistically significant improvement in OS and PFS for the NALIRIFOX arm over Gem+NabP arm. (Onivyde, 2024)
CPT/HCPCS:
J9205Injection, irinotecan liposome, 1 mg
References: Frampton James.(2020) Liposomal Irinotecan: A Review in Metastatic Pancreatic Adenocarinoma. Drugs (2020) 80:1007–1018. doi. 10.1007/s40265-020-01336-6.

Mercade, TM, Chen, L, Li, C, et. al.,(2020) Liposomal Irinotecan + 5-FU/LV in Metastatic Pancreatic Cancer: Subgroup Analysis of Patient, Tumor, and Previous Treatment Characteristics in the Pivotal NAPOLI-1 Trial. Pancreas. 2020 January; 49(1): 62-75.

National Comprehensive Cancer Network (NCCN)(2023) National Comprehensive Cancer Network, Inc. 2023 Practice Guidelines in Oncology Irinotecan Liposome. Available at https://www.nccn.org. Accessed April 13, 2023.

National Comprehensive Cancer Network (NCCN).(2021) NCCN Clinical Practice Guidelines in Oncology: Pancreatic Adenocarcinoma. Version 2.2021. https://www.nccn.org/professionals/physician_gls/pdf/pancreatic.pdf. Accessed February 25, 2021.

Onivyde (irinotecan liposome) [prescribing information]. Cambridge, MA: Merrimack Pharmaceuticals, Inc. 2015.

Tossey, JC, Reardon, J, VanDeusen, JB, et al.(2019) Comparison of conventional versus liposomal irinotecan in combination with fluorouracil for advanced pancreatic cancer: a single-institution experience. Med Oncol. 2019 Sep 7; 36(10); 87. doi. 10.1007/s12032-019-1309-6.

Wang-Gillam A, Hubner RA, Siveke,JT, et. al.(2019) NAPOLI-1 phase 3 study of liposomal irinotecan in metastatic pancreatic cancer: Final overall survival analysis and characteristics of long-term survivors. European Journal of Cancer, 2019:108; 78-87.

Woo, W, Carey, E, and Minsiq, Choi.(2019) Spotlight on liposomal irinotecan for metastatic pancreatic cancer: Patient Selection and Perspectives. Onco Targets Ther. 2019; 12: 1455-1463.
Group specific policy will supersede this policy when applicable. This policy does not apply to the Wal-Mart Associates Group Health Plan participants or to the Tyson Group Health Plan participants.
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