Medical Policies - Prescription Drugs


Onivyde (irinotecan liposome)

Number:RX502.042

Effective Date:10-01-2018

Coverage:

*CAREFULLY CHECK STATE REGULATIONS AND/OR THE MEMBER CONTRACT*

Medical policies are a set of written guidelines that support current standards of practice. They are based on current peer-reviewed scientific literature. A requested therapy must be proven effective for the relevant diagnosis or procedure. For drug therapy, the proposed dose, frequency and duration of therapy must be consistent with recommendations in at least one authoritative source. This medical policy is supported by FDA-approved labeling and nationally recognized authoritative references. These references include, but are not limited to: MCG care guidelines, DrugDex (IIb level of evidence or higher), NCCN Guidelines (IIb level of evidence or higher), NCCN Compendia (IIb level of evidence or higher), professional society guidelines, and CMS coverage policy.

When the requested chemotherapeutic agent is being utilized in a regimen in combination with other chemotherapeutic agents, the entire regimen (including dose, frequency, and duration) must be consistent with recommendations in at least one authoritative source, including but not limited to FDA labeling and nationally recognized compendia or clinical guidelines such as National Comprehensive Cancer Network (NCCN) and CMS coverage policy. HCSC may require a provider submit documentation from nationally recognized compendia, clinical guidelines, or active Phase III clinical trials supporting the requested regimen.

Onivyde® (irinotecan liposome) may be considered medically necessary for the treatment of adult patients (age 18 or older) with pancreatic adenocarcinoma and an Eastern Cooperative Oncology Group Performance Status (ECOG-PS) rating of 0-2, when given in combination with fluorouracil (5-FU) and leucovorin (LV) as:

Second-line therapy for disease progression following treatment with either gemcitabine-based therapy or fluoropyrimidine-based therapy that did not include irinotecan; OR

Recurrence therapy for local recurrence after resection or metastatic disease with or without local recurrence, occurring ≥6 months since completion of primary therapy; OR

Recurrence therapy for metastatic disease with or without local recurrence, occurring <6 months since completion of primary therapy, if previously treated with either gemcitabine-based therapy or fluoropyrimidine-based therapy that did not include irinotecan.

Onivyde® (irinotecan liposome) is considered experimental, investigational and/or unproven for all other indications, including but not limited to use as a single agent for the treatment of metastatic adenocarcinoma of the pancreas.

Description:

Onivyde® (irinotecan liposome), also known as MM-398 or “nal-IRI”, is a topoisomerase 1 inhibitor encapsulated in a lipid bilayer vesicle or liposome. Topoisomerase 1 relieves torsional strain in deoxyribonucleic acid (DNA) by inducing single strand breaks. Irinotecan and its active metabolite SN-38 bind reversibly to the topoisomerase 1-DNA complex and prevent re-ligation of the single-strand breaks, leading to exposure time-dependent double-strand DNA damage and cell death. (1)

Eastern Cooperative Oncology Group (ECOG) Performance Scale

Assessment of the patient’s daily living abilities, also known as the patient’s performance status, including their ability to take care of themselves, daily activity, and physical ability, such as walking, working, etc., is required for a new treatment method, as well continued or repeated therapy. (2) One such measurement tool is the ECOG Performance Scale, developed in 1982. The following Table 1 displays the grade levels and performance scale descriptions.

Table 1. Eastern Cooperative Oncology Group (ECOG) Performance Scale(2)

Grade

ECOG Performance Status

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, e.g., 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 selfcare; confined to bed or chair more than 50% of waking hours.

4

Completely disabled; cannot carry on any selfcare; totally confined to bed or chair.

5

Dead.

Regulatory Status

Onivyde® (irinotecan liposome) was approved by the U.S. Food and Drug Administration (FDA) on October 22, 2015 for the use with fluorouracil (5-FU) and leucovorin (LV) in the treatment of patients with metastatic adenocarcinoma of the pancreas after disease progression following gemcitabine-based therapy. The labeling includes a boxed warning about the risks of severe neutropenia and diarrhea. To date, the safety and effectiveness has not been established in pediatric patients. (1)

Rationale:

Onivyde® (Irinotecan Liposome) was approved by the U.S. Food and Drug Administration (FDA) based on a three-arm, randomized, open-label trial in patients with metastatic pancreatic adenocarcinoma with documented disease progression, after gemcitabine or gemcitabine-based therapy. (1) Eligibility criteria included Karnofsky Performance Status (KPS) ≥70, serum bilirubin within institution limits of normal, and albumin ≥3.0 g/dL. Patients were randomized to receive Onivyde plus fluorouracil (5-FU) and leucovorin (LV) (5-FU/LV), Onivyde, or 5-FU/LV. Randomization was stratified by ethnicity, KPS (70-80 vs 90-100), and baseline albumin level (≥ 4 g/dL vs 3.0-3.9 g/dL). Patients randomized to Onivyde/5-FU/LV received Onivyde 70 mg/m2 as an intravenous (IV) infusion over 90 minutes, followed by LV 400 mg/m2 IV over 30 minutes, followed by 5-FU 2400 mg/m2 IV over 46 hours, every 2 weeks. The Onivyde dose of 70 mg/m2 is based on irinotecan free base (equivalent to 80 mg/m2 of irinotecan as the hydrochloride trihydrate). Patients randomized to Onivyde as a single agent received Onivyde 100 mg/m2 as an IV infusion over 90 minutes every 3 weeks. Patients randomized to 5-FU/LV received leucovorin (LV) 200 mg/m2 IV over 30 minutes, followed by 5-FU 2000 mg/m2 IV over 24 hours, administered on Days 1, 8, 15 and 22 of a 6-week cycle. Patients homozygous for the UGT1A1 28 allele initiated Onivyde at a reduced dose (50 mg/m2 Onivyde, if given with 5-FU/LV or 70 mg/m2 Onivyde as a single agent). When Onivyde was withheld or discontinued for adverse reactions, 5-FU was also withheld or discontinued. When the dose of Onivyde was reduced for adverse reactions, the dose of 5-FU was reduced by 25%. Treatment continued until disease progression or unacceptable toxicity was noted. The major efficacy outcome measure was overall survival (OS) with two pair-wise comparisons: Onivyde versus 5-FU/LV and Onivyde/5-FU/LV versus 5-FU/LV. Additional efficacy outcome measures were progression-free survival (PFS) and objective response rate (ORR). Tumor status assessments were conducted at baseline and every 6 weeks thereafter. The trial was initiated as a two-arm study and amended after initiation to include a third arm (Onivyde/5FU/LV). The comparisons between the Onivyde/5-FU/LV and the 5-FU/LV arms are limited to patients enrolled in the 5-FU/LV arm after this protocol amendment.

Four hundred seventeen patients were randomized to Onivyde/5-FU/LV (N=117), Onivyde (N=151), or 5-FU/LV (N=149). Baseline demographics and tumor characteristics for the 236 patients randomized to Onivyde/5-FU/LV or 5-FU/LV (N=119) after the addition of the third arm to the study were a median age of 63 years (range 34-81 years) and with 41% ≥ 65 years of age; 58% were men; 63% were White, 30% were Asian, 3% were Black or African American, and 5% were other. Mean baseline albumin level was 3.97 g/dL, and baseline KPS was 90-100 in 53% of patients. Disease characteristics included liver metastasis (67%) and lung metastasis (31%). A total of 13% of patients received gemcitabine in the neoadjuvant/adjuvant setting only, 55% of patients had 1 prior line of therapy for metastatic disease, and 33% of patients had 2 or more prior lines of therapy for metastatic disease. All patients received prior gemcitabine (alone or in combination with another agent), 54% received prior gemcitabine in combination with another agent, and 13% received prior gemcitabine in combination with nab-paclitaxel. Statistically significant improvement in OS for the Onivyde/5-FU/LV arm over the 5-FU/LV arm was identified (Table 2). There was no improvement in OS for the Onivyde arm over the 5-FU/LV arm (hazard ratio=1.00, p-value=0.97 (two-sided log-rank test).

Table 2: Efficacy Results (1)

Onivyde/5-FU/LV (N=117)

5-FU/LV (N=119)

Overall Survival

Number of Deaths, n (%)

77 (66)

86 (72)

Median OS (months)

6.1

4.2

(95% CI)

(4.8, 8.5)

(3.3, 5.3)

Hazard Ratio (95% CI)

0.68 (0.50, 0.93)

p-value (log-rank test)

0.014

Progression-Free Survival

Death or Progression, n (%)

83 (71)

94 (79)

Median PFS (months)

3.1

1.5

(95% CI)

(2.7, 4.2)

(1.4, 1.8)

Hazard Ratio (95% CI)

0.55 (0.41, 0.75)

Objective Response Rate

Confirmed Complete or Partial Response n (%)

9 (7.7%)

1 (0.8%)

Table Key: 5-FU/LV=5-fluorouracil/leucovorin; CI=confidence interval; OS=overall survival; PFS= progression-free survival, N=number

In 2013, Ko et al. performed a multinational phase 2 study of nanoliposomal irinotecan sucrosofate (PEP02, MM-398) for patients with gemcitabine-refractory metastatic pancreatic cancer. (3) This phase 2 study evaluated PEP02 monotherapy as a second-line treatment for pancreatic cancer. Patients who had metastatic pancreatic adenocarcinoma, Karnofsky performance status ≥70, and had progressed following gemcitabine-based therapy were eligible. Intravenous injection of PEP02 120 mg m(-2) was given every 3 weeks. Simon 2-stage design was used. The primary objective was 3-month survival rate (OS 3-month). A total of 40 patients were enrolled. The most common severe adverse events included neutropenia, abdominal pain, asthenia, and diarrhea. Three patients (7.5%) achieved an objective response, with an additional 17 (42.5%) demonstrating stable disease for a minimum of two cycles. Ten (31.3%) of 32 patients with an elevated baseline CA19-9 had a >50% biomarker decline. The study met its primary end point with an OS of 75%, with median PFS and OS of 2.4 and 5.2 months, respectively. The study determined that PEP02 demonstrates moderate antitumour activity with a manageable side effect profile for metastatic, gemcitabine-refractory pancreatic cancer patients.

In 2016, Wang et al. (4) published results from a global, phase 3, randomized, open-label trial that included 76 sites in 14 countries. Eligible patients with metastatic pancreatic ductal adenocarcinoma previously treated with gemcitabine-based therapy were randomly assigned (1:1) using an interactive web response system at a central location to receive either nanoliposomal irinotecan monotherapy (120 mg/m(2) every 3 weeks, equivalent to 100 mg/m(2) of irinotecan base) or 5-FUand folinic acid. A third arm consisting of nanoliposomal irinotecan (80 mg/m(2), equivalent to 70 mg/m(2) of irinotecan base) with 5-FU and folinic acid every 2 weeks was added later (1:1:1), in a protocol amendment. Randomization was stratified by baseline albumin, Karnofsky performance status, and ethnic origin. Treatment was continued until disease progression or intolerable toxic effects were noted. The primary endpoint was OS, assessed in the intention-to-treat population. The primary analysis was planned after 305 events. Safety was assessed in all patients who had received the study drug. Between Jan 11, 2012, and Sept 11, 2013, 417 patients were randomly assigned either nanoliposomal irinotecan plus 5-FU and folinic acid (n=117), nanoliposomal irinotecan monotherapy (n=151), or 5-FU and folinic acid (n=149). After 313 events, median OS in patients assigned nanoliposomal irinotecan plus 5-FU and folinic acid was 6.1 months (95% CI 4.8-8.9) vs 4.2 months (3.3-5.3) with 5-FU and folinic acid (hazard ratio 0.67, 95% CI 0.49-0.92; p=0.012). Median OS did not differ between patients assigned nanoliposomal irinotecan monotherapy and those allocated 5-FU and folinic acid (4.9 months [4.2-5.6] vs 4.2 months [3.6-4.9]; 0.99, 0.77-1.28; p=0.94). The grade 3 or 4 adverse events that occurred most frequently in the 117 patients assigned nanoliposomal irinotecan plus 5-FU and folinic acid were neutropenia (32 [27%]), diarrhea (15 [13%]), vomiting (13 [11%]), and fatigue (16 [14%]). The authors noted that nanoliposomal irinotecan in combination with 5-FU and folinic acid extends survival with a manageable safety profile in patients with metastatic pancreatic ductal adenocarcinoma who previously received gemcitabine-based therapy.

Summary of Evidence

Onivyde® (irinotecan liposome) was evaluated in clinical studies involving 417 people with advanced pancreatic cancer. People treated with a combination of Onivyde and the anti-cancer drugs fluorouracil (5-FU) and leucovorin (LV) lived an average of 6.1 months, compared to 4.2 months among those treated with 5-FU or LV alone. There was no survival improvement for those who received only Onivyde compared to those who received 5-FU/LV. In addition, patients receiving Onivyde plus 5-FU/LV had a delay in the amount of time to tumor growth compared to those who received 5-FU/LV. The FDA label specifies it is not indicated as a single agent for individuals with metastatic pancreatic cancer.

Professional Guidelines and Position Statements

National Comprehensive Cancer Network (NCCN) Guidelines and NCCN Drugs & Biologics Compendium

The 2018 NCCN Guidelines (V1.2018) on Pancreatic Adenocarcinoma and the NCCN Drugs & Biologics Compendium recommend Onyvide for the following indications (5, 6):

“Second-line therapy in combination with fluorouracil and leucovorin for locally advanced or metastatic disease in patients with good performance status, disease progression and ECOG- PS 0-2 who were previously treated with:

o Fluoropyrimidine-based therapy and no prior irinotecan. (Category 2A recommendation)

o Gemcitabine-based therapy.” (Category 1 recommendation)

“Recurrence therapy for local recurrence in the pancreatic bed after resection or metastatic disease with or without local recurrence ≥ 6 months from completion of primary therapy in patients with good performance status in combination with fluorouracil and leucovorin if ECOG PS 0-2.” (Category 2A recommendation)

“Recurrence therapy for metastatic disease with or without local recurrence less than 6 months from completion of primary therapy in patients with good performance status and ECOG 0-2

o In combination with fluorouracil and leucovorin if previously treated with gemcitabine-based therapy.

o In combination with fluorouracil and leucovorin if previously treated with fluoropyrimidine-based therapy that did not include irinotecan.” (Category 2A recommendation)

Contract:

Each benefit plan, summary plan description or contract defines which services are covered, which services are excluded, and which services are subject to dollar caps or other limitations, conditions or exclusions. Members and their providers have the responsibility for consulting the member's benefit plan, summary plan description or contract to determine if there are any exclusions or other benefit limitations applicable to this service or supply. If there is a discrepancy between a Medical Policy and a member's benefit plan, summary plan description or contract, the benefit plan, summary plan description or contract will govern.

Coding:

CODING:

Disclaimer for coding information on Medical Policies

Procedure and diagnosis codes on Medical Policy documents are included only as a general reference tool for each policy. They may not be all-inclusive.

The presence or absence of procedure, service, supply, device or diagnosis codes in a Medical Policy document has no relevance for determination of benefit coverage for members or reimbursement for providers. Only the written coverage position in a medical policy should be used for such determinations.

Benefit coverage determinations based on written Medical Policy coverage positions must include review of the member’s benefit contract or Summary Plan Description (SPD) for defined coverage vs. non-coverage, benefit exclusions, and benefit limitations such as dollar or duration caps.

CPT/HCPCS/ICD-9/ICD-10 Codes

The following codes may be applicable to this Medical policy and may not be all inclusive.

CPT Codes

None

HCPCS Codes

J9205, [Deleted 1/2017: C9474]

ICD-9 Diagnosis Codes

Refer to the ICD-9-CM manual

ICD-9 Procedure Codes

Refer to the ICD-9-CM manual

ICD-10 Diagnosis Codes

Refer to the ICD-10-CM manual

ICD-10 Procedure Codes

Refer to the ICD-10-CM manual


Medicare Coverage:

The information contained in this section is for informational purposes only. HCSC makes no representation as to the accuracy of this information. It is not to be used for claims adjudication for HCSC Plans.

The Centers for Medicare and Medicaid Services (CMS) does not have a national Medicare coverage position. Coverage may be subject to local carrier discretion.

A national coverage position for Medicare may have been developed since this medical policy document was written. See Medicare's National Coverage at <http://www.cms.hhs.gov>.

References:

1. FDA–Onivyde (irinotecan liposome) Product Label. Food and Drug Administration (November 2015). Available at: <http://www.fda.gov> (accessed March 23, 2018).

2. ECOG Performance Scale/Status (1982). Developed by the Eastern Cooperative Oncology Group, Comis RL, Group Chair. Available at: <http://www.ecog-acrin.org> (accessed May 9, 2018)

3. Ko AH, Tempero MA, Shan YS, et al. A multinational phase 2 study of nanoliposomal irinotecan sucrosofate (PEP02, MM-398) for patients with gemcitabine-refractory metastatic pancreatic cancer. Br J Cancer. 2013 Aug 20; 109(4):920-5. PMID 23880820

4. Wang-Gillam A, Li CP, Bodoky G, et al. 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. 2016 Feb 6; 387(10018):545-57. PMID: 26615328

5. National Comprehensive Cancer Network. NCCN Clinical Practice Guideline for Pancreatic Adenocarcinoma. V.1.2018. Available online at: <http://www.nccn.org> (accessed May 9, 2018).

6. Onivyde. NCCN Drugs & Biologics Compendium. National Comprehensive Cancer Network 2018. Available at: <http://www.nccn.org> (accessed May 9, 2018).

Policy History:

Date Reason
10/1/2018 Document updated with literature review. The following change(s) were made to Coverage: 1) Updated to include National Comprehensive Cancer Network recommended indications. References 2, 5-6 added; one reference removed.
4/1/2017 Reviewed. No changes.
4/1/2016 New medical document. Onivyde ® (Irinotecan Liposome) may be considered medically necessary in combination with fluorouracil (5-FU) and leucovorin (LV), for the treatment of adult patients (age 18 or older) with metastatic adenocarcinoma of the pancreas after disease progression following gemcitabine-based therapy. Onivyde ® (Irinotecan Liposome) is considered experimental, investigational, and/or unproven for all other indications, including but not limited to use as a single agent for the treatment of metastatic adenocarcinoma of the pancreas.

Archived Document(s):

Title:Effective Date:End Date:
Onivyde (Irinotecan Liposome)04-01-201709-30-2018
Onivyde (Irinotecan Liposome)04-01-201603-31-2017
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