Irinotecan Liposome Injection (Onivyde)

Number: 0902

Table Of Contents

Policy
Applicable CPT / HCPCS / ICD-10 Codes
Background
References

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Policy

1. Criteria for Initial Approval

   1. Ampullary adenocarcinoma

      Aetna considers irinotecan liposome injection (Onivyde) medically necessary as subsequent therapy for disease progression when the member has good performance status (Eastern Cooperative Oncology Group [ECOG] 0-1 (see Appendix), with good biliary drainage and adequate nutritional intake) and pancreatobiliary and mixed type in combination with fluorouracil and leucovorin when previously treated with prior:

      1. Gemcitabine-based therapy; or
      2. Fluoropyrimidine-based therapy if no prior irinotecan; or
      3. Oxaliplatin-based therapy if no prior irinotecan.
         

   2. Pancreatic adenocarcinoma

      Aetna considers irinotecan liposome injection (Onivyde) medically necessary as subsequent therapy for the treatment of locally advanced or metastatic pancreatic adenocarcinoma or for local recurrence of disease after resection, in combination with fluorouracil and leucovorin, when the member has an Eastern Cooperative Oncology Group (ECOG) performance status score 0-2 (see Appendix) and when any of the following criteria is met:

      1. The member previously received fluoropyrimidine-based therapy that did not include irinotecan; or
      2. The member previously received gemcitabine-based therapy; or
      3. If 6 months or more from completion of primary therapy as alternate therapy not previously used.

   Aetna considers all other indications as experimental and investigational (for additional information, see Experimental and Investigational and Background sections).

2. Continuation of Therapy

   Aetna considers continuation of irinotecan liposome injection (Onivyde) therapy medically necessary for an indication listed in Section I when there is no evidence of unacceptable toxicity or disease progression while on the current regimen.

Note: This policy does not apply to irinotecan hydrochloride (Camptosar).

Dosage and Administration

Onivyde (irinotecan liposome injection) is available in a 43mg/10mL single dose vial injection for intravenous use.

The recommended dosage of Onivyde (irinotecan liposone injection) is as follows:

Metastatic adenocarcinoma of the pancreas

• Administer Onyvide 70 mg/m2 via intravenous infusion over 90 minutes every two weeks.
• The recommended Onivyde starting does in individuals known to be homozygous for UGT1A1*28 is 50 mg/m2 every two weeks. Increase the dose of Onivyde to 70 mg/m2 as tolerated in subsequent cycles.
• There is no recommended dose of Onivyde for persons with serum bilirubin above the upper limit of normal.
• Premedicate with a corticosteroid and an anti‐emetic 30 minutes prior to Onivyde infusion.
• Safety and effective has not been established in pediatrics.
• Do not substitute Onivyde for other drugs containing irinotecan HCl.

Source: Ipsen Biopharmaceuticals, 2017

Experimental and Investigational

Aetna considers irinotecan liposome injection experimental and investigational for the following (not an all-inclusive list):

• Biliary tract cancer
• Brain tumors (e.g., astrocytoma, glioblastoma, gliosarcoma, malignant glioma, and oligodendroglioma)
• Breast cancer
• Breast cancer brain metastases
• Colon cancer
• Esophageal squamous cell carcinoma
• First-line treatment of pancreatic cancer
• Gastric cancer
• Lung cancer (e.g., small cell lung cancer)
• Medullary thyroid carcinoma
• Neuroblastoma
• Osteosarcoma
• Ovarian cancer
• Pediatric sarcoma (e.g., Ewing's sarcoma)
• Rectal cancer
• Rhabdomyosarcoma
• Wilms tumor.

Aetna considers bevacizumab combined with irinotecan experimental and investigational for the treatment of intracranial tumors because the effectiveness of this approach has not been established.

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Table:

CPT Codes / HCPCS Codes / ICD-9 Codes

Code	Code Description
Other CPT codes related to the CPB :
96413 - 96417	Chemotherapy administration, intravenous infusion technique
HCPCS codes covered if selection criteria are met:
J9205	Injection, irinotecan liposome, 1 mg
Other HCPCS codes related to the CPB:
J0640	Injection, leucovorin calcium, per 50mg
J9035	Injection, bevacizumab, 10 mg
J9190	Injection, fluorouracil, 500mg
J9196	Injection, gemcitabine hydrochloride (accord), not therapeutically equivalent to j9201, 200 mg
J9201	Injection, gemcitabine HCl, 200 mg
ICD-10 codes covered if selection criteria is met :
C24.1	Malignant neoplasm of ampulla of Vater
C25.0 - C25.9	Malignant neoplasm of pancreas
ICD-10 codes not covered for indications listed in the CPB (not all-inclusive):
C15.3 – C15.9	Malignant neoplasm of esophagus [Esophageal squamous cell carcinoma]
C16.0 - C16.9	Malignant neoplasm of stomach
C18.0 - C20	Malignant neoplasm of colon and rectum
C24.0, C24.8 - C24.9	Malignant neoplasm of other and unspecified parts of biliary tract
C34.00 - C34.92	Malignant neoplasm of bronchus and lung
C41.0 - C41.9	Malignant neoplasm of bones of skull and face [Ewing's sarcoma and osteosarcoma]
C45.0	Mesothelioma of pleura
C49.0 - C49.9	Malignant neoplasm of connective and other soft tissue [pediatric sarcoma]
C50.011 - C50.019, C50.111 - C50.119, C50.211 - C50.219, C50.311 - C50.319, C50.411 - C50.419, C50.511 - C50.519, C50.611 - C50.619, C50.811 - C50.819, C50.911 - C50.919	Malignant neoplasm of breast (female)
C56.1 - C56.9	Malignant neoplasm of ovary [ovarian cancer]
C64.0 – C64.9	Malignant neoplasm of kidney, except renal pelvis [Wilms tumor]
C71.0 - C71.9	Malignant neoplasm of brain [Glioblastoma]
C73	Malignant neoplasm of thyroid gland [medullary thyroid carcinoma]
C74.00 - C74.92	Malignant neoplasm of adrenal gland [neuroblastoma]
C79.31 - C79.32	Secondary malignant neoplasm of brain and cerebral meninges

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Background

U.S. Food and Drug Administration (FDA)-Approved Indications

• Onivyde is indicated, in combination with fluorouracil and leucovorin, for the treatment of patients with metastatic adenocarcinoma of the pancreas after disease progression following gemcitabine-based therapy.

Limitation of Use: Onivyde is not indicated as a single agent for the treatment of patients with metastatic adenocarcinoma of the pancreas.

Compendial Uses

Ampullary adenocarcinoma

• Subsequent therapy for disease progression in patients 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:

  • gemcitabine-based therapy; or
  • fluoropyrimidine-based therapy if no prior irinotecan; or
  • oxaliplatin-based therapy if no prior irinotecan

Pancreatic adenocarcinoma

• Subsequent therapy in combination with fluorouracil and leucovorin for locally advanced or metastatic disease in patients with good performance status (ECOG PS 0-2) and disease progression who were previously treated with:

  • fluoropyrimidine-based therapy and no prior irinotecan; or
  • gemcitabine-based therapy
    
    

• Therapy in combination with fluorouracil and leucovorin for local recurrence in the pancreatic operative bed or recurrent metastatic disease after resection in patients with good performance status (ECOG PS 0-2):

  • if less than 6 months from completion of primary therapy and previously treated with gemcitabine-based therapy; or
  • if less than 6 months from completion of primary therapy and previously treated with fluoropyrimidine-based therapy that did not include irinotecan; or
  • if ≥ 6 months from completion of primary therapy as alternate systemic therapy not previously used

Onivyde (liposomal irinotecan) is a topoisomerase I inhibitor incapsulated in a lipid bilayer vesicle. This enables higher concentrations in the body at lower doses compared to irinotecan hydrochloride.

Topoisomerase I is a cellular enzyme involved in maintaining the topographic structure of DNA during translation, transcription, and mitosis. It helps to relieve the torsional strain in the DNA helix during replication and RNA transcription by inducing single strand breaks. Onivyde (liposomal irinotecan) and its active metabolite bind with topoisomerase I, thereby preventing the re‐ligation of the single strand breaks which leads to DNA damage and cell death.

Irinotecan liposome injection (also known MM-398 and PEP02) is a liposomal formulation of the topoisomerase I inhibitor irinotecan.  It is a nanotherapeutic agent that consists of 80,000 molecules of the chemotherapeutic irinotecan encapsulated in a 100-mm liposome sphere.  This nanoliposomal formulation has been demonstrated in pre-clinical studies to enhance pharmacokinetics and tumor bio-distribution of both irinotecan and its active metabolite SN-38 when compared with the free form of the drug, with less accumulation in many of the target organs associated with toxic side effects.  MM-398 has also shown increased effectiveness and tolerable toxicity when compared with free irinotecan in an orthotopic pancreatic cancer mouse model (Hann et al, 2007).  It has also been studied for the treatment of other malignancies.

Pancreatic Cancer

Onivyde (liposomal irinotecan) is indicated in combination with fluorouracil and leucovorin for the treatment of patients with metastatic adenocarcinoma of the pancreas after disease progression following gemcitabine-based therapy.

Tsai et al (2011) noted that systemic therapy for advanced pancreatic cancer has been largely disappointing owing to the unfavorable pharmacokinetic profile and poor penetration of current chemotherapeutic agents, as well as the fragile patient population with compromised tolerance to toxic chemotherapies.  Nanovectors can provide passive drug delivery through abnormal tumor neo-vasculature microanatomy or active targeting via binding to receptors or macromolecules associated with the tumor.  In such a manner, nanovector-based therapy may not only modulate the pharmacokinetics and therapeutic index of chemotherapeutic agents but also provide new treatment options in patients with advanced pancreatic cancer.  These investigators presented the rationale and currently available clinical results of nanovector-based therapies (including PEP02) to highlight the potential use of this class of agent in patients with advanced pancreatic cancer.

Ko and colleagues (2013) stated that MM-398 (PEP02) has improved pharmacokinetics and tumor bio-distribution of the free drug.  In a phase II clinical trial, these researchers evaluated PEP02 monotherapy as second-line treatment for pancreatic cancer.  Patients who had metastatic pancreatic adenocarcinoma, Karnofsky performance status (PS) greater than or equal to 70, and had progressed following gemcitabine-based therapy were eligible.  Intravenous injection of PEP02 120 mg/m2 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 (SD) for a minimum of 2 cycles.  Ten (31.3 %) of 32 patients with an elevated baseline CA19-9 had a greater than 50 % biomarker decline.  The study met its primary end-point with an OS(3-month) of 75 %, with median progression-free survival (PFS) and overall survival (OS) of 2.4 and 5.2 months, respectively.  The authors concluded that PEP02 demonstrated moderate anti-tumor activity with a manageable side effect profile for metastatic, gemcitabine-refractory pancreatic cancer patients.  They stated that given the limited treatment options available to this patient population, a phase III clinical trial of PEP02 (MM-398), referred to as NAPOLI-1, is currently underway.

On October 22, 2015, the FDA approved Onivyde (irinotecan liposome injection), in combination with fluorouracil and leucovorin, to treat patients with metastatic pancreatic cancer who have been previously treated with gemcitabine-based chemotherapy.  Onivyde is not approved for use as a single agent for the treatment of patients with metastatic pancreatic cancer.  The effectiveness of Onivyde was demonstrated in a 3-arm, randomized, open-label study of 417 patients with metastatic pancreatic adenocarcinoma whose cancer had grown after receiving gemcitabine or a gemcitabine-based therapy.  The study was designed to examine if patients receiving Onivyde + fluorouracil/leucovorin or Onivyde alone lived longer than those receiving fluorouracil/leucovorin.  Patients treated with Onivyde + fluorouracil/leucovorin lived an average of 6.1 months, compared to 4.2 months for those treated with only fluorouracil/leucovorin.  There was no survival improvement for those who received only Onivyde compared to those who received fluorouracil/leucovorin.  In addition, patients receiving Onivyde + fluorouracil/leucovorin had a delay in the amount of time to tumor growth compared to those who received fluorouracil/leucovorin.  The average time for those receiving Onivyde + fluorouracil/leucovorin was 3.1 months compared to 1.5 months for those receiving fluorouracil/leucovorin.

The safety of Onivyde was evaluated in 398 patients who received either Onivyde + fluorouracil/leucovorin, Onivyde alone or fluorouracil/leucovorin.  The most common side effects of treatment with Onivyde included diarrhea, fatigue, vomiting, nausea, decreased appetite, stomatitis and pyrexia.  Onivyde was also found to result in lymphopenia and neutropenia; death due to sepsis following neutropenia has been reported in patients treated with Onivyde.  The labeling for Onivyde includes a boxed warning to alert health care professionals about the risks of severe neutropenia and diarrhea.

Black Box Warning

• Fatal neutropenic sepsis occured in 0.8% of patients receiving Onivyde. Severe or life threatening neutropenic fever or sepsis occured in 3% and severe or life threatening neutropenia occured in 20% of patients receiving Onivyde in combination with fluorouracil and leucovorin. WIthout Onivyde for absoute neutrophil count below 1500/mm³ or neutropenic fever. Monitor blood cell counts periodically during treatment.
• Severe diarrhea occured in 13% of patients receiving Onivyde in combination with fluorouracil and leucovorin. Do not administer Onivyde to patients with bowel obstruction. Withhold Onivyde for diarrhea of Grade 2‐4 severity. Administer loperamide for late diarrhea of any severity. Administer atropine, if not contraindicated, for early diarrhea of any severity.

Warnings and Precautions

• Intersitial lung disease (ILD): Fatal ILD has occured in patients receiving irinotecan HCl. Discontinue Onivyde if ILD is diagnosed.
• Severe hypersensitivity reaction: Permanently discontinue Onivyde for severe hypersensitivity reactions.
• Embryo‐fetal toxicity: Can cause fetal harm. Advise femaltes of reproductive potential of the potential risk to a fetus and to use effective contraception.

Experimental and Investigational Indications

Bevacizumab Combined with Irinotecan for the Treatment of Intracranial Tumors

Dong and associates (2019) stated that bevacizumab (BVZ) plus irinotecan is a new beneficial chemotherapy strategy for patients with malignant glioma.  In a systematic review and meta-analysis, these investigators examined the risk of adverse vascular events in adults with malignant glioma treated with BVZ plus irinotecan.  The Cochrane Library, Embase and PubMed were searched, and relevant trials were identified up to June 2018.  Two investigators screened all titles and abstracts for possible inclusion and extracted data independently.  A total of 6 studies were included, and 5 of them in the control group using BVZ alone or BVZ with temozolomide.  Three systems were used to evaluate the quality of evidence and the level of recommendation.  The Oxford Centre for Evidence-Based Medicine Levels of Evidence (2009) system was used to classify the evidence into 5 levels (classes I to V).  The star system from the Newcastle-Ottawa Scale was used to assess methodological quality.  The GRADE profiler was used to evaluate the overall body of evidence.  The results demonstrated that BVZ plus irinotecan therapy did not significantly affect the risk of systemic adverse events (AEs; odds ratio [OR], 1.17; 95 % confidence interval [CI]: 0.43 to 3.18).  Patients treated with BVZ plus irinotecan had a similar risk of hemato-toxicity (OR, 1.06; 95 % CI: 0.26 to 4.38), thrombocytopenia (OR, 1.07; 95 % CI: 0.25 to 4.63), and hypertension (OR, 1.34; 95 % CI: 0.28 to 6.36) compared with the control group (those treated without irinotecan).  Thrombosis occurred more frequently in patients treated with BVZ plus irinotecan compared with the control group (OR, 3.23; 95 % CI: 1.47 to 7.12).  The authors concluded that the risk of systemic AEs was not significantly different between patients with malignant glioma treated with BVZ plus irinotecan and the control group.  The risks of hemato-toxicity, thrombocytopenia, and hypertension were similar in the 2 groups.  The risk of thrombosis was higher in patients treated with BVZ plus irinotecan.  Monitoring for thrombosis and administering anti-coagulant therapy as necessary merit promotion for patients with malignant glioma receiving treatment with BVZ plus irinotecan.

In a meta-analysis, Xu and colleagues (2020) examined the efficacy and side effects of BVZ combined with irinotecan in the treatment of pediatric patients (younger than 21 years of age) with recurrent, progressive or refractory intracranial tumors.  These investigators searched for articles published before October 31, 2018 in PubMed, Embase, Cochrane library and Web of Science.  They selected relevant literature on the combination of BVZ and irinotecan in the treatment of children with intracranial tumors.  Objective response was evaluated by combining PR, CR, SD and progressive disease (PD), and survival time was evaluated by combining OS and PFS; common side effects were also analyzed.  All data included were obtained from single-arm data, with no control groups.  A total of 13 studies involving 272 patients were included.  These researchers found that out of 41 % patients who showed an objective response following the BVZ therapy combined with irinotecan, 28 % achieved a PR, 13 % achieved a CR, 32 % showed a SD, and 43 % had a PD; PFS and OS were 6.47 and 11.9 months, respectively; gastro-intestinal (GI) dysfunction, leukopenia and hypertension were the 3 most common AEs, accounting for 36.7 %, 33.6 % and 22.1 %, respectively, whereas Musculo-skeletal disorders had the lowest occurrence, accounting for 3.9 %.  The authors concluded that BVZ combined with irinotecan-based chemotherapy had a better response and prolonged survival in the treatment of pediatric intracranial tumors than radiation therapy or chemotherapy; GI dysfunction, leukopenia and hypertension were the toxic side effects with the highest incidence.  These researchers stated that these findings were promising.  They anticipated that BVZ combined with irinotecan‐based chemotherapy would provide new insights into pediatric brain tumors treated with anti-angiogenesis therapies; they encouraged the inclusion of these patients in clinical trials using BVZ combined with irinotecan‐based chemotherapy.

The authors stated that this study had several drawbacks.  First, this meta-analysis and systematic review lacked relevant randomized controlled trials (RCTs), and as only single‐arm studies have been included, the effect sizes comparable to other treatments were unavailable.  The 2nd drawback was the small number of related studies and sample sizes because of a relatively low incidence rate of pediatric tumors.

Crotty and co-workers (2020) retrospectively reviewed 36 pediatric patients treated with temozolomide, irinotecan, and bevacizumab (TIB) at Seattle Children's Hospital from 2009 to 2018 and analyzed survival using the Kaplan-Meier method.  Molecular profiling was performed by targeted DNA sequencing and toxicities, steroid use, and palliative care utilization were evaluated.  Median age at diagnosis was 10.9 years (18 months to 18 years).  Genetic alterations were detected in 26 genes and aligned with recognized molecular subgroups including H3 K27M-mutant (n = 12), H3F3A G34-mutant (n = 2), IDH-mutant (n = 4), and hypermutator profiles (n = 4).  A total of 15 patients (42 %) completed 12 planned cycles of maintenance.  Side effects associated with chemotherapy delay or modifications included thrombocytopenia (28 %) and nausea/vomiting (19 %), with temozolomide dosing most frequently modified.  Median EFS and OS was 16.2 and 20.1 months, with shorter survival observed in diffuse intrinsic pontine gliomas (DIPG; 9.3 and 13.3 months, respectively).  Survival at 1, 2, and 5 years was 80 %, 10 % and 0 % for DIPG and 85 %, 38 %, and 16 % for other pediatric high-grade glioma (pHGG).  The authors concluded that this single-center experience demonstrated tolerability of this 3-drug regimen, with prolonged survival in DIPG compared to historical single-agent temozolomide.  These researchers stated that pHGG survival was comparable to analogous 3-drug regimens and superior to historical agents; however, cure was rare.

Biliary Tract Cancer

Taghizadeh And colleagues (2020) noted that therapeutic options are limited for advanced, metastatic biliary tract cancer.  The pivotal NAPOLI-1 trial demonstrated the superior clinical benefit of nano-liposomal irinotecan (Nal-IRI) in gemcitabine-pretreated patients with metastatic pancreatic ductal adenocarcinoma (PDAC); however, the anti-tumor activity of Nal-IRI in biliary tract cancer is unknown.  In a retrospective, multi-center, cohort study, these researchers examined the efficacy of Nal-IRI in biliary tract cancer.  They identified patients with metastatic biliary tract adenocarcinoma who were treated with Nal-IRI in combination with 5-fluorouracil and folinic acid following tumor progression under standard therapy at one of the study centers between May 2016 and January 2019.  These investigators evaluated disease control rate (DCR), PFS, and OS.  There were a total of 14 patients; the median age at the time of diagnosis and the median age at the initiation of Nal-IRI were 59.3 and 60.0 years, respectively.  Nal-IRI in combination with 5-fluorouracil and folinic acid was administered as 2nd-, 3rd-, 4th-, and 5th-line treatment in 6 (43 %), 5 (36 %), 2 (14 %), and 1 (7 %) patient with metastatic disease, respectively.  The objective DCR with Nal-IRI was 50 % (7/14 patients); 6 patients (43 %) had PR, and 1 patient (7 %) had SD; PD was observed in 7 patients.  The median PFS and median OS following Nal-IRI initiation were 10.6 and 24.1 months, respectively.  The authors concluded that the findings of this retrospective analysis provided the first evidence that Nal-IRI might exhibit a clinical meaningful anti-tumor activity in metastatic biliary tract cancer.  Moreover, these researchers stated that further studies and clinical trials are needed to understand the complex tumor biology and improve OS in biliary tract cancer.

The authors stated that this study had several drawbacks.  First, it was a non-randomized and retrospective analysis of a multi-center registry.  Second, the study cohort was small (n = 14) and lacked an adequate control group.  Third, the cohort was skewed to young age and was dominated by female patients.  Moreover, the disease assessment was performed by the local departments of radiology and not by a blinded central review.  These researchers stated that it is important to emphasize that this analysis may contain survivorship bias since it was based on the data of patients who had already received a median of 2 prior treatments and experienced a relatively long median OS of 35.7 months.

Brain Tumors

Noble et al (2014) evaluated nanoliposomal irinotecan as an intravenous treatment in an orthotopic brain tumor model.  Nanoliposomal irinotecan was administered intravenously in the intra-cranial U87MG brain tumor model in mice, and irinotecan and SN-38 levels were analyzed in malignant and normal tissues.  Tissue analysis demonstrated favorable properties for nanoliposomal irinotecan, including an almost 11-fold increase in tumor area under the plasma drug concentration-time curve (AUC) for drug compared with free irinotecan and 35-fold selectivity for tumor versus normal tissue exposure.  As a therapy for orthotopic brain tumors, nanoliposomal irinotecan showed a mean survival time of 54.2 versus 29.5 days for free irinotecan.  A total of 33 % of the animals receiving nanoliposomal irinotecan showed no residual tumor by the end of the study compared with no survivors in the other groups.  The authors concluded that nanoliposomal irinotecan administered systemically provided significant pharmacologic advantages and may be an effective therapy for brain tumors.

Breast Cancer

Zhang et al (2013) constructed a kind of PEG-coated irinotecan cationic liposomes for investigating its effectiveness and mechanism of action in the treatment of breast cancer in pre-clinical models.  Evaluations were performed on the MDA-MB231 breast cancer cells, the xenografted MDA-MB231 cancer cells in female nude mice and Sprague-Dawley (SD) rat. The liposomes were characterized through assays of cytotoxicity, intracellular uptake, nuclei morphology, anti-tumor activities, pharmacokinetics and tissue distribution. The zeta potential of PEG-coated irinotecan cationic liposomes was approximately 23 mV.  The PEG-coated irinotecan cationic liposomes were approximately 66 nm in diameter, significantly increased the intracellular uptake of irinotecan, and showed strong inhibitory effect on MDA-MB231 breast cancer cells.  A significant anti-tumor efficacy in the xenografted MDA-MB231 breast cancer cells in nude mice was evidenced by intravenous administration of PEG-coated irinotecan cationic liposomes.  PEG-coated irinotecan cationic liposomes also improved the irinotecan blood circulation time and showed an enhanced drug concentration in tumor.  The authors concluded that PEG-coated irinotecan cationic liposomes had significant inhibitory effect against breast cancer in-vitro and in-vivo, hence providing a new strategy for treating breast cancer.

Breast Cancer Brain Metastases

Shah and colleagues (2018) stated that in women, breast cancer is the most common cancer diagnosis and 2nd commonest cause of cancer death.  More than 50 % of breast cancer patients will develop metastases to the bone, liver, lung, or brain.  Breast cancer brain metastases (BCBM) confers a poor prognosis, as current therapeutic options of surgery, radiation, and chemotherapy rarely significantly extend life and are considered palliative.  Within the realm of chemotherapy, the past 10 years has seen an explosion of novel chemotherapeutics involving targeting agents and unique dosage forms.  These investigators provided a historical overview of BCBM chemotherapy, reviewed the mechanisms of new agents such as poly-ADP ribose polymerase inhibitors, cyclin-dependent kinase 4/6 inhibitors, phosphatidyl inositol 3-kinaseinhibitors, estrogen pathway antagonists for hormone-receptor positive BCBM; tyrosine kinase inhibitors, antibodies, and conjugates for HER2+ BCBM; re-purposed cytotoxic chemotherapy for triple-negative BCBM; and the utilization of these new agents and formulations in ongoing clinical trials.  The authors discussed the  mechanisms of novel dosage formulations such as nanoparticles, liposomes, pegylation, the concepts of enhanced permeation and retention, and drugs utilizing these concepts involved in clinical trials; they stated that these new treatments provide a promising outlook in the treatment of BCBM.

Colon Cancer

Klinz et al (2013) stated that tumor hypoxia is strongly linked to aggressive disease progression and resistance to therapy.  Positron emission tomography (PET) imaging with hypoxia tracers such as [18F]fluoroazomycin arabinoside (FAZA) allows for non-invasive quantification of tumor hypoxia during treatment.  These researchers and others have previously shown that treatments with longer lasting camptothecin formulations reduced tumor hypoxia after either single or multiple treatment cycles.  In this study, these investigators evaluated the kinetics and magnitude of hypoxia changes in tumors after treatment with irinotecan sucrosofate liposome injection (MM-398), which has shown an extended plasma half-life and higher intra-tumoral deposition in animal models relative to free pro-drug and compared it to the effects of free irinotecan at equivalent exposure levels.  FAZA-PET/CT was used for longitudinal monitoring of tumor hypoxia changes in the HT29 mouse colon cancer xenograft model over a 21-day period following weekly chemotherapy administrations of either MM-398 (5 and 10 mg/kg) or free irinotecan (50 mg/kg).  These dosages were predicted to result in comparable SN-38 exposure in either plasma or tumor based on a mechanistic pharmacokinetic model of MM-398 and free irinotecan.  Baseline levels of FAZA uptake in tumors were similar across treatment groups.  Significant differences in tumor FAZA uptake were observed between these groups as early as day 7 following initiation of treatment, with increased FAZA uptake seen in tumors treated with free irinotecan.  In contrast, differences in tumor volume only became statistically significant on day 16.  MM-398 at 10 mg/kg was the most effective treatment for control of tumor volume and also minimized changes in FAZA uptake at all time-points.  Background FAZA levels in the muscle were consistent over time across all treatment groups (0.78 ± 0.18 % injected dose (ID)/g, 0.81 ± 0.11 % ID/g and 0.71 ± 0.20 % ID/g).  However, normalization with muscle signal did not improve quantification of FAZA uptake differences in tumors.  Tumor-specific hypoxia status at the study end-point was confirmed by co-staining for CA9 and EF5 levels, which were, as expected, highly correlated.  Average EF5 intensity/tumor area was lowest in the MM-398 (10 mg/kg) treatment group, while being highest in the irinotecan (50 mg/kg) treatment group.  The authors concluded that the findings of this study demonstrated the feasibility of performing longitudinal and repeated tumor hypoxia assessment using FAZA-PET imaging.  Treatment with MM-398, but not free irinotecan, led to significant changes in the tumor microenvironment as measured by reduced hypoxia levels that occurred far earlier than anatomical changes assessed by tumor volume.  Moreover, they stated that imaging of hypoxia levels after anti-cancer therapy with MM-398 has the potential to allow early assessment of treatment activity.  The role of irinotecan sucrosofate liposome injection (MM-398) for the treatment of colon cancer needs to be further investigated in well-designed studies.

Esophageal Squamous Cell Carcinoma

In a phase-I clinical trial, Liu et al (2021) determined the maximum-tolerated dose (MTD), dose-limiting toxicities (DLTs), preliminary efficacy, and pharmacokinetics (PK) of LY01610, a novel liposome-encapsulated irinotecan, in patients with advanced esophageal squamous cell carcinoma (ESCC). This study was carried out in 2 stages. In the dose-escalation stage, patients with advanced ESCC refractory or intolerant to previous chemotherapy received escalating doses of LY01610. A recommended dose based on patient tolerance was then expanded in the 2nd stage. LY01610 was administered intravenously every 2 weeks, except that the 1st cycle in dose escalation was 3 weeks to allow observation of DLTs. A total of 24 patients were enrolled across 4 dose levels (30, 60, 90 and 120 mg/m2). The DLTs included vomiting and febrile neutropenia, and the MTD was 90 mg/m2. The most common grade 3/4 AEs were leukopenia in 6 patients (25.0 %), anemia in 6 patients (25.0 %) and neutropenia in 5 patients (20.8 %); 1 patient achieved CR, and 4 had PR, including 1 patient receiving LY01610 at the starting dose of 30 mg/m2. Compared with conventional irinotecan, the PK profile of LY01610 was characterized by increased and prolonged exposure of total irinotecan and the active metabolite SN-38 in plasma. The authors concluded that LY01610 demonstrated manageable toxicity and promising anti-tumor activity in patients with advanced ESCC. These researchers stated that further validation in randomized trials of LY01610 as single agent or in combination with other anti-cancer agents in treating ESCC patients is needed.

Ewing's Sarcoma Family of Tumors

Kang and colleagues (2015) determined the pharmacokinetics and the anti-tumor activity of MM-398, a nanoliposomal irinotecan (nal-IRI) in pediatric cancer models. Mouse plasma and tissue pharmacokinetics of nal-IRI and the current clinical formulation of irinotecan were characterized.  In-vivo activity of irinotecan and nal-IRI was compared in xenograft models (3 each in nu/nu mice) of Ewing's sarcoma family of tumors (EFT), neuroblastoma (NB), and rhabdomyosarcoma (RMS).  SLFN11 expression was assessed by Affymetrix HuEx arrays, Taqman RT-PCR, and immunoblotting.  Plasma and tumor concentrations of irinotecan and SN-38 (active metabolite) were approximately 10-fold higher for nal-IRI than for irinotecan.  Two doses of NAL-IRI (10 mg/kg/dose) achieved CRs maintained for more than 100 days in 24 of 27 EFT-xenografted mice.  Event-free survival (EFS) for mice with RMS and NB was significantly shorter than for EFT.  High SLFN11 expression has been reported to correlate with sensitivity to DNA damaging agents; median SLFN11 mRNA expression was over 100-fold greater in both EFT cell lines and primary tumors compared with NB or RMS cell lines or primary tumors.  Cytotoxicity of SN-38 inversely correlated with SLFN11 mRNA expression in 20 EFT cell lines.  The authors concluded that in pediatric solid tumor xenografts, nal-IRI demonstrated higher systemic and tumor exposures to SN-38 and improved anti-tumor activity compared with the current clinical formulation of irinotecan.  They stated that clinical studies of nal-IRI in pediatric solid tumors (especially EFT) and correlative studies to determine if SLFN11 expression can serve as a biomarker to predict nal-IRI clinical activity are needed.

There is a phase-I clinical trial of "Nanoliposomal CPT-11 (NL CPT-11) in Patients With Recurrent High-Grade Gliomas” that has been completed (last verified December 2014). The gliomas studied included anaplastic astrocytoma, anaplastic oligodendroglioma, glioblastoma, and gliosarcoma,

There is a phase-I clinical trial of “MM-398 Plus Cyclophosphamide in Pediatric Solid Tumors” that is currently recruiting participants (last verified February 2017). The solid tumors being studied included Ewing's sarcoma, neuroblastoma, osteosarcoma, and rhabdomyosarcoma

In addition, there is a phase-I/II clinical trial of “Pembrolizumab Plus Chemotherapy in Patients With Advanced Cancer (PembroPlus)” that is ongoing, but not recruiting participants (last verified June 2017). The malignancies being studied included breast cancer, ovarian cancer, pancreatic cancer, sarcoma, and small cell lung cancer.

Gastric Cancer

Yamaguchi and associates (2019) noted that while uridine diphosphate glucuronosyltransferase (UGT) 1A1 is a key enzyme in the metabolism of irinotecan, relationship between UGT1A1 genotype and safety and efficacy of irinotecan monotherapy in patients with advanced gastric cancer (AGC) is not clarified.  These researchers examined the safety and efficacy of irinotecan monotherapy as 3rd-line treatment in AGC patients, who were tested for UGT1A1*6 and *28 genotype from 2009 to 2014.  Among 74 patients of the subjects, the genotypes of UGT1A1 were wild-type (WT) in 37 patients (50 %), single heterozygosity (SH) in 27 (36.5 %) and double heterozygosity or homozygosity (Homo/DH) in 10 (13.5 %).  The initial dose of irinotecan was reduced in 10 patients (27 %) with WT, in 9 (33 %) with SH, and in 7 (70 %) with Homo/DH.  Median OS was 6.9 months, 6.3 months, and 2.8 months in the WT, SH and Homo/DH genotypes, associated with median time to treatment failure of 2.4 months, 2.3 months, and 1.3 months, respectively.  Among 36 patients with measurable lesion, disease control rates were 47.6 %, 41.7 % and 33.3 % in the WT, SH and Homo/DH genotypes.  Grade-3 or higher AEs of special interest were neutropenia (13 %, 22 %, and 64 % for the WT, SH and Homo/DH genotypes), febrile neutropenia (2 %, 7 %, and 50 %) and diarrhea (6 %, 5 %, and 21 %).  The authors concluded that since Homo/DH patients showed unfavorable clinical outcomes associated with a high risk of grade-3 or higher AEs, irinotecan may not be administered as 3rd-line or later-line therapy in AGC patients with the UGT1A1 Homo/DH polymorphism.

The authors stated that this study had several drawbacks.  This was a retrospective study that could not collect the precise data of AEs and quality of life (QOL), no data of pharmacokinetics, and there were no pre-specified criteria for dose reduction, rest and discontinuation of irinotecan.  The small sample size at single-center, especially, including only 10 UGT1A1 Homo/DH patients, could not adjust the difference in patient’s background even by multi-variate analysis.  These drawbacks might have led to bias in this study.

Nakano and colleagues (2020) stated that it is unclear if the UGT1A1 status, single heterozygous (SH) or wild type (WT), is associated with the efficacy and toxicity of irinotecan monotherapy in AGC.  In a retrospective, multi-center study, these investigators examined the association between clinical outcomes (safety and efficacy) and UGT1A1 status in patients who received irinotecan monotherapy.  They assessed AGC patients who received irinotecan monotherapy between January 2011 and December 2017.  Efficacy was assessed according to OS and PFS; toxicity was graded using the Common Toxicity Criteria for Adverse Events (version 4.0).  A total of 100 patients were evaluated (62 and 38 patients with UGT1A1 WT and SH, respectively).  In the WT and SH groups, the irinotecan dose was reduced in 19 (30.6 %) and 18 (47.2 %) patients (p = 0.135), respectively; treatment was delayed due to AEs in 19 (30.6 %) and 13 (34.2 %) patients (p = 0.826), respectively; the median PFS was 3.15 and 3.25 months (HR, 0.734; 95 % CI: 0.465 to 1.158; p = 0.184), respectively; and the median OS was 10.4 and 7.26 months (HR, 1.137; 95 % CI: 0.752 to 1.721; p = 0.543), respectively.  Severe hematological AEs (grade greater than or equal to 3) were significantly more frequent in the SH group than in the WT group (63 % versus 36 %; p = 0.008), while severe non-hematological AEs was not significantly different (16.0 % versus 6.5 %; p = 0.173).  The authors concluded that there was no significant difference in the efficacy of irinotecan monotherapy between UGT1A1 WT and UGT1A1 SH; however, UGT1A1 SH was associated with a high frequency of severe hematological toxicity.  Moreover, these researchers stated that further well-designed, large-scale prospective studies are needed to clarify the association between UGT1A1 SH and risk of hematological AEs.

The authors stated that this study had several drawbacks.  First, the inherent biases in a retrospective study could not be eliminated.  However, these investigators tried to decrease the bias by collecting many patients from several institutions.  To the authors’ knowledge, this study was the largest retrospective study to analyze the impact of UGT1A1 status on the safety and efficacy of irinotecan monotherapy in AGC.  Second, many novel drugs (such as oxaliplatin, nab-paclitaxel, ramucirumab, nivolumab, and TAS-102) have been approved for gastric cancer in Japan during the study period, and this has influenced the guidelines and clinical practice.

Glioblastoma

Elinzano et al (2021) stated that liposomal formulations may improve the solubility and bioavailability of drugs potentially increasing their ability to cross the blood-brain barrier (BBB). In a phase-I clinical trial, these researchers determined the MTD and preliminary efficacy of pegylated nano-liposomal irinotecan (nal-IRI)+metronomic temozolomide (TMZ) in patients with recurrent glioblastoma. Patients with glioblastoma who progressed after at least 1 line of therapy were eligible. All patients received TMZ 50 mg/m2/day until disease progression; 3 dose levels of nal-IRI were planned, 50, 70, and 80 mg/m2, intravenously every 2 weeks. Patients were accrued in a 3+3 design. The study included a preliminary assessment after the first 13 evaluable patients. The trial would be terminated early if 0 or 1 responses were observed in these patients. A total of 12 patients were treated over 2 dose levels (nal-IRI 50 and 70 mg/m2). At dose level 2, nal-IRI 70 mg/m2, 2 of 3 patients developed DLTs including 1 patient who developed grade-4 neutropenia and grade-3 diarrhea and anorexia and 1 patient with grade-3 diarrhea, hypokalemia fatigue, and anorexia. Accrual to dose level 1 was expanded to 9 patients. The Drug Safety Monitoring Board (DSMB) reviewed the data of the initial 12 patients -- there were 0/12 responses (0 %) and the median PFS was 2 months, and accrual was stopped. The authors concluded that the MTD of nal-IRI was 50 mg/m2 every 2 weeks with TMZ 50 mg/m2/day; the DLTs were diarrhea and neutropenia. No activity was observed at interim analysis and the study was terminated.

Lung Cancer

Leonard and colleagues (2017) stated that liposomal irinotecan (irinotecan liposome injection, nal-IRI) is designed for extended circulation relative to irinotecan and for exploiting discontinuous tumor vasculature for enhanced drug delivery to tumors. Following tumor deposition, nal-IRI is taken up by phagocytic cells followed by irinotecan release and conversion to its active metabolite, SN-38.  Sustained inhibition of topoisomerase 1 by extended SN-38 exposure as a result of delivery by nal-IRI is hypothesized to enable superior anti-tumor activity compared with traditional topoisomerase 1 inhibitors such as conventional irinotecan and topotecan. These researchers evaluated the anti-tumor activity of nal-IRI compared with irinotecan and topotecan in pre-clinical models of small-cell lung cancer (SCLC) including in a model pre-treated with carboplatin and etoposide, a 1st-line regimen used in SCLC.  Nal-IRI demonstrated anti-tumor activity in xenograft models of SCLC at clinically relevant dose levels and resulted in complete response (CR) or partial response (PR) in DMS-53, DMS-114, and NCI-H1048 cell line-derived models as well as in 3 patient-derived xenograft models.  The anti-tumor activity of nal-IRI was superior to that of topotecan in all models tested, which generally exhibited limited control of tumor growth and was superior to irinotecan in 4 of 5 models.  Furthermore, nal-IRI demonstrated anti-tumor activity in tumors that progressed following treatment with topotecan or irinotecan, and demonstrated significantly greater anti-tumor activity than both topotecan and irinotecan in NCI-H1048 tumors that had progressed on previous carboplatin plus etoposide treatment.  The authors concluded that these findings supported the clinical development of nal-IRI in patients with SCLC.

Paz-Ares et al (2022) stated that RESILIENT is a phase-II/III clinical trial examining the safety, tolerability, and effectiveness of liposomal irinotecan monotherapy in patients with SCLC and disease progression on/after 1st-line platinum-based therapy. These researchers presented results from part 1 of the RESILIENT Trial, which is an open-label, single-arm study with safety run-in evaluation with dose-exploration and dose-expansion phases. Patients 18 years of age or older with ECOG PS of 0/1; those with asymptomatic central nervous system (CNS) metastases were eligible. The primary objectives were to evaluate safety and tolerability and recommend a dose for further development. Efficacy endpoints were objective response rate (ORR), PFS, and OS. During dose exploration, 5 patients received intravenous (IV) liposomal irinotecan at 85 mg/m2 (deemed not tolerable; dose-limiting toxicity [DLT]) and 12 patients received 70 mg/m2 (deemed tolerable). During dose expansion, 13 additional patients received IV liposomal irinotecan at 70 mg/m2 . Of these 25 patients (median age [range], 59.0 [48.0 to 73.0] years, 92.0 % with metastatic disease), 10 experienced grade 3 or higher treatment-related treatment-emergent AEs (TEAEs), most commonly diarrhea (20.0 %) and neutropenia (16.0 %), and 3 had serious treatment-related TEAEs, of whom 2 died. ORR was 44.0 % (95 % CI: 24.40 to 65.07; 1 CR, 10 PRs) and median (95 % CI) PFS and OS were 3.98 (1.45 to 4.24) months and 8.08 (5.16 to 9.82) months, respectively. The authors concluded that overall, no new safety signals were identified with liposomal irinotecan, and anti-tumor activity was promising. These investigators stated that part 2 of the RESILIENT Trial, a randomized, controlled, phase-III clinical trial of liposomal irinotecan versus topotecan, is ongoing.

Medullary Thyroid Carcinoma

Iwase and Maitani (2012) stated that medullary thyroid carcinoma is a rare endocrine tumor, which shows over-expression of somatostatin receptor subtype 2.  There is no systemic therapy for medullary thyroid carcinoma.  Previously, these investigators reported that octreotide-PEG liposomes loaded with irinotecan, which target somatostatin receptor subtype 2, showed high therapeutic efficacy for medullary thyroid carcinoma xenografts compared with free irinotecan or non-targeted non-PEGylated liposomal irinotecan.  In this study, these researchers evaluated octreotide-PEG liposomes loaded with irinotecan in terms of the bio-distribution of irinotecan and its active metabolite, and its therapeutic efficacy, compared with PEGylated liposomes.  Furthermore, to elucidate the effect of octreotide ligand after cellular association, the authors assessed the cytotoxicity in tumor cells and the inhibition of protein phosphorylation in the tumor cells and xenografts using empty octreotide-PEG liposomes, which were loaded with no drug.  Octreotide-PEG liposomes loaded with irinotecan significantly improved median survival compared with PEGylated liposomes.  In tumor tissue at 6 hours after injection, octreotide-PEG liposome-treated mice showed significantly higher concentrations of irinotecan and 7-ethyl-10-hydrocamptothecin compared with PEGylated liposome-treated mice, indicating that octreotide-PEG liposomes accumulated rapidly and to a high level in the tumor.  Furthermore, empty octreotide-PEG liposome inhibited the phosphorylation of p70S6K in-vitro and in-vivo.  The authors concluded that these findings indicated that octreotide-PEG liposomal irinotecan has dual functions with targeted tumor delivery and assistance of cellular cytotoxicity, which led to higher therapeutic efficacy than PEGylated liposomes for medullary thyroid carcinoma xenografts.  The role of liposomal irinotecan in the treatment of medullary thyroid cancer needs to be further investigated in well-designed studies.

Wilms Tumor

Wang et al (2021) noted that the prognosis of relapsed or refractory (R/R) pediatric Wilms tumor (WT) is dismal, and new salvage therapies are needed.  In a retrospective, single-arm study, these researchers examined the effectiveness of the combination of irinotecan and a doxorubicin hydrochloride liposome regimen for the treatment of R/R pediatric WT.  This trial enrolled R/R pediatric WT patients who were treated with the irinotecan-doxorubicin hydrochloride liposome (AI) regimen (doxorubicin hydrochloride liposomes 40 mg/m2 per day, day 1, and irinotecan 50 mg/m2 per day with 90-min infusion, days 1 to 5; this regimen was repeated every 3 weeks) at Sun Yat-Sen University Cancer Center from July 2018 to September 2020.  The response was defined as the best-observed response after at least 2 cycles according to the Response Evaluation Criteria of Solid Tumors (RECIST 1.1), and toxicity was evaluated according to the Common Terminology Criteria for Adverse Events (CTCAE 4.03).  A total of 16 patients (male/female, 8/8) with a median age of 4.2 years (0.5 to 11 years) with R/R disease were enrolled in this study, including 14 patients with relapsed disease and 2 patients with refractory disease.  These subjects received 1 to 8 courses (median of 3 courses) of the AI regimen; 14 subjects were assessable for response: 2 with CR, 5 with PR, 2 with SD, and 5 with PD.  The ORR was 50 % (2 CR, 5 PR), and the disease control rate was 64 % (2 CR, 5 PR, and 2 SD); 7 out of 14 patients (50 %) were alive at the last follow-up, ranging from 2.6 to 32.4 months.  The median PFS and median OS were 3.5 months (range of 0.5 to 12 months) and 8 months (range of 1 to 28 months), respectively; 16 patients were assessable for toxicity, with the most common grade 3 or 4 AEs being alopecia (62 %), leukopenia (40 %), abdominal pain (38 %), diarrhea (23 %), and mucositis (16 %), etc.  No fatal AEs were observed.  The authors concluded that irinotecan and doxorubicin hydrochloride liposome regimens exhibited positive effectiveness on R/R pediatric WT with well-tolerated toxicity; these researchers stated that a prospective clinical trial is needed. 

The authors stated that this study had 2 main drawbacks.  As a retrospective, single-arm study, the comparison could not be carried out because this study lacked a control group, which may cause selection bias due to the non-randomized design.  In addition, limited sample sizes were enrolled in this study.

Other Experimental Indications

OPTUMInsight HTP Alert on Onivyde (2015) states that “Onivyde is currently undergoing studies to treat breast cancer, pediatric sarcoma, colorectal cancer, lung cancer, and malignant glioma.  The drug is also in clinical trials for the first-line treatment of pancreatic cancer”.

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Appendix

Table: ECOG Performance Status

Grade	ECOG
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 housework, office work
2	Ambulatory and capable of all selfcare 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

Source: Oken MM, Creech RH, Tormey DC, et al. Toxicity and response criteria of the Eastern Cooperative Oncology Group. Am J Clin Oncol. 1982;5(6):649-655.

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References