Coverage Policy Manual
Policy #: 2021022
Category: Pharmacy
Initiated: March 2021
Last Review: March 2022
  Trabectedin (e.g., Yondelis)

Description:
Trabectedin is an antineoplastic alkaloid that binds the DNA minor groove and bends it to the major groove resulting in the inhibition of DNA transcription and repair.  It is indicated for the treatment of patients with unresectable or metastatic liposarcoma or leiomyosarcoma who received a prior anthracycline-containing regimen.  
 
Sarcomas are a rare and heterogenous group of malignant tumors that arise from skeletal and extraskeletal connective tissues.  There are many sites that can be affected, including the retroperitoneum, chest wall, head, neck and subcutaneous tissues.  In adults the most common histologic types of retroperitoneal sarcomas are liposarcoma and leiomyosarcoma, followed by undifferentiated/unclassified soft tissue sarcoma.
 
Well-differentiated (low-grade) liposarcomas are the most common, followed by dedifferentiated liposarcomas.  Low grade liposarcomas have no potential to metastasize; they are referred to as atypical lipomatous tumors when they arise in the body/wall/trunk or extremities.  They do however have a propensity for local recurrence in the retroperitoneum/mediastinum and spermatic cord.  
 
Dedifferentiated liposarcomas are high-grade tumors.  They have a higher local recurrence rate than well-differentiated low grade liposarcomas and the potential to metastasize and a sixfold higher risk of death.   It is thought that a high-grade dedifferentiated liposarcomas arise form well-differentiated liposarcomas and that well-differentiated liposarcomas can recur as the more aggressive dedifferentiated subtype.
 
Leiomyosarcomas of the retroperitoneum generally arise from the inferior vena cava, its tributaries, or any small vessel.  They often present as a mass and are usually of a large size when diagnosed. Lung (more than liver) metastases, are sometimes observed at the time of presentation or appear relatively quickly after diagnosis.  Leiomyosarcomas may also arise from the wall of the gastrointestinal tract or from the uterus. In this situation, they are visceral rather than retroperitoneal and have a greater risk of peritoneal spread and metastasis to the liver.  
 
Regulatory Status
 
Trabectedin was approved by the U.S. Food and Drug Administration (FDA) in October 23, 2015. It was the first in treatment for liposarcoma at that time.  
 
Coding
 
J9352       Injection, trabectedin, 0.1 mg

Policy/
Coverage:
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 January 2022
 
Meets Primary Coverage Criteria Or Is Covered For Contracts Without Primary Coverage Criteria
 
The use of trabectedin meets member benefit certificate primary coverage criteria that there be scientific effectiveness as indicated for the treatment of adult patients that meet the criteria indicated below:
 
Initiation of therapy
 
1. Must be >18 yrs. (FDA 2015)
2. Left ventricular ejection fraction (LVEF) is within normal limits prior to initiating therapy and will be assessed at regular intervals (e.g. every 3 months) during treatment. (FDA 2015)
3. Must be used as a single-agent therapy. (NCCN 2A)
4. Must have documented diagnosis of unresectable or metastatic liposarcoma or leiomyosarcoma with a prior anthracycline-containing regimen (e.g., doxorubicin etc) (FDA 2015)
5. In Myxoid Liposarcoma – (NCCN 2A)
· Extremity/Body Wall, Head/Neck - neoadjuvant/adjuvant therapy for primary tumors or local recurrence given as:
· preoperative systemic therapy, with or without radiation therapy (RT), for stage III or select stage IV (any T, N1, M0) resectable disease with acceptable functional outcomes
· primary treatment as systemic therapy or chemoradiation for stage II, III, or select stage IV (any T, N1, M0) resectable disease with adverse functional outcomes or unresectable disease
· adjuvant systemic therapy in addition to RT following primary treatment of surgery for stage III or select stage IV (any T, N1, M0) resectable disease with acceptable functional outcomes
· adjuvant systemic therapy, to be considered postoperatively if given primary treatment with either preoperative RT or preoperative systemic therapy with RT for stage III or select stage IV (any T, N1, M0) resectable disease with acceptable functional outcomes
· adjuvant systemic therapy in addition to RT given postoperatively if given primary treatment with preoperative systemic therapy for stage III or select stage IV (any T, N1, M0) resectable disease with acceptable functional outcomes
· adjuvant systemic therapy to be considered following primary treatment with amputation/radical resection for stage II, III, or select stage IV (any T, N1, M0) resectable disease with adverse functional outcomes or unresectable primary disease
· adjuvant systemic therapy for resectable disease with acceptable functional outcomes following primary treatment for stage II, III, or select stage IV (any T, N1, M0) resectable disease with adverse functional outcomes or unresectable primary disease
· Retroperitoneal/Intra-Abdominal - neoadjuvant/adjuvant therapy as:
· preoperative systemic therapy for resectable disease (primary or recurrent)
· postoperative systemic therapy to be considered in histologies with high risk for metastatic disease (not recommended for low-grade tumors)
· as postoperative systemic therapy for resectable recurrent disease to be considered for histologies with high risk of metastatic disease or history of several recurrences with a high risk for local recurrences
6. In Soft Tissue Sarcoma (STS): as palliative therapy in the treatment of One of the following sub-types of STS: (NCCN 1-2A)
· Advanced, metastatic extremity/body wall or head/neck soft tissue sarcoma with disseminated metastases. OR
· Angiosarcoma OR
· Rhabdomyosarcoma when used for ANY ONE of the following:
· Subsequent therapy for advanced or metastatic pleomorphic rhabdomyosarcoma OR
· Non-pleomorphic rhabdomyosarcoma.
· Retroperitoneal/Intra-Abdominal and used as subsequent therapy for advanced, recurrent unresectable, or metastatic disease with disseminated metastases. OR
· Solitary fibrous tumor. OR
7. Uterine sarcoma and meets ALL the following: (NCCN 2A)
· Diagnosis of uterine leiomyosarcoma
· Is used as a single-agent therapy after a prior anthracycline containing regimen (e.g. doxorubicin, etc) for ANY ONE of the following:
· Has a radiologically isolated vaginal/pelvic recurrence.
· Is not suitable for primary surgery
· Has unresectable isolated metastases or disseminated disease.
· Consider postoperatively for resectable isolated metastases
 
Continuation of therapy
 
Continuation of treatment with trabectedin beyond 12 months after initiation of therapy for the treatment of unresectable or metastatic liposarcoma or leiomyosarcoma meets member certificate primary coverage criteria when the following are met:
· Initial approval criteria have been met; AND
· Absence of unacceptable toxicity from use of this medication such as cardiomyopathy, rhabdomyolysis, hepatotoxicity and/or severe hepatic impairment, capillary leak syndrome, severe neutropenia/neutropenic sepsis, extravasation resulting in tissue necrosis, etc.
· Durable clinical benefit has been demonstrated while receiving trabectedin, with partial or complete response or stable disease.
· Left ventricular ejection fraction (LVEF) has not had an absolute decrease of > 15% from baseline or is not below the lower limit of normal (LLN) with an absolute decrease of > (LVEF results must be within the previous 3 months).
 
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 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 of specified criteria (See policy #2000030).
 
Dosage and Administration (FDA 2015)
 
Dosing is 1.5 mg/m2 administered IV over 24 hours through a central venous line (CVL) every 21 days, until disease progression.
 
Hepatic Impairment: Dose is 0.9 mg/m2 in patients with moderate hepatic impairment (bilirubin levels greater than 1.5 times to 3 times the upper limit of normal, and AST and ALT less than 8 times the upper limit of normal.
 
Do not administer trabectedin to patients with severe hepatic impairment (bilirubin levels above 3 times the upper limit of normal, and any AST and ALT).
 
Effective Prior to January 2022
 
Meets Primary Coverage Criteria Or Is Covered For Contracts Without Primary Coverage Criteria
 
The use of trabectedin (Yondelis®) meets member benefit certificate primary coverage criteria that there be scientific effectiveness as indicated for the treatment of adult patients that meet the criteria indicated below:
 
Initiation of therapy
1. Must be >18 yrs.
2. Left ventricular ejection fraction (LVEF) is within normal limits prior to initiating therapy and will be assessed at regular intervals (e.g. every 3 months) during treatment.
3. Must be used as a single-agent therapy.
4. Must have documented diagnosis of unresectable or metastatic liposarcoma or leiomyosarcoma with a prior anthracycline-containing regimen (e.g., doxorubicin etc)
5. In Soft Tissue Sarcoma (STS): as palliative therapy in the treatment of One of the following sub-types of STS
· Advanced, metastatic extremity/body wall or head/neck soft tissue sarcoma with disseminated metastases. OR
· Angiosarcoma OR
· Rhabdomyosarcoma when used for ANY ONE of the following:
· Subsequent therapy for advanced or metastatic pleomorphic rhabdomyosarcoma OR
· Non-pleomorphic rhabdomyosarcoma.
· Retroperitoneal/Intra-Abdominal and used as subsequent therapy for advanced or metastatic disease with disseminated metastases. OR
· Solitary fibrous tumor. OR
6. Uterine sarcoma and meets ALL the following:
· Diagnosis of uterine leiomyosarcoma
· Is used as a single-agent therapy after a prior anthracycline containing regimen (e.g. doxorubicin, etc) for ANY ONE of the following:
· Has a radiologically isolated vaginal/pelvic recurrence.
· Is not suitable for primary surgery
· Has unresectable isolated metastases or disseminated disease.
 
Continuation of therapy
Continuation of treatment with trabectedin beyond 12 months after initiation of therapy for the treatment of unresectable or metastatic liposarcoma or leiomyosarcoma meets member certificate primary coverage criteria when the following are met:
· Initial approval criteria have been met; AND
· Absence of unacceptable toxicity from use of this medication such as cardiomyopathy, rhabdomyolysis, hepatotoxicity and/or severe hepatic impairment, capillary leak syndrome, severe neutropenia/neutropenic sepsis, extravasation resulting in tissue necrosis, etc.
· Durable clinical benefit has been demonstrated while receiving trabectedin, with partial or complete response or stable disease.
· Left ventricular ejection fraction (LVEF) has not had an absolute decrease of > 15% from baseline or is not below the lower limit of normal (LLN) with an absolute decrease of > (LVEF results must be within the previous 3 months).
 
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 of specified criteria (See policy #2000030).
 
Dosage and Administration
Dosing is 1.5 mg/m2 administered IV over 24 hours through a central venous line (CVL) every 21 days, until disease progression.
 
Hepatic Impairment: Dose is 0.9 mg/m2 in patients with moderate hepatic impairment (bilirubin levels greater than 1.5 times to 3 times the upper limit of normal, and AST and ALT less than 8 times the upper limit of normal.
 
Do not administer trabectedin to patients with severe hepatic impairment (bilirubin levels above 3 times the upper limit of normal, and any AST and ALT)
 
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 trabectedin does not meet primary coverage criteria that there be scientific evidence of effectiveness for all other indications except those listed above.
 
For members with contracts without primary coverage criteria, the use of trabectedin is investigational. Investigational services are specific contract exclusions in most member benefit certificates of coverage.

Rationale:
ET743-SAR-3007 (NCT 01343277) Phase III trial
In this multicenter study, the comparison of the efficacy and safety of trabectedin versus dacarbazine in a randomized phase III trial patients with advanced liposarcoma or leiomyosarcoma was performed.  Patients 15 yrs or older with locally advanced or metastatic liposarcoma or leiomyosarcomas that had been previously treated with a combination of an anthracycline and ifosfamide or an anthracycline plus one or more additional cytotoxic chemotherapy regimen(s). Patients had to have adequate bone marrow, renal and liver functions as well as an ECOG performance status score of 1 or lower.  Exclusion criteria included known CNS metastasis, myocardial infarct within 6 months before enrollment, and New York Heart Association class II or greater heart failure.  
 
There were 518 patients randomly assigned in a 2:1 ration to receive either trabectedin (n=345) at a starting dose of 1.5 mg/m2 as a 24 hour IV or dacarbazine (n=173) at a starting dose of 1g/m2 as a 20 to 120-minute IV infusion. Study drug was administered on day 1 of each 21-day treatment cycle.  All trabectedin dosed were administered via a central venous line after dexamethasone 20 mg premedication given. In the final analysis of progression free survival (PFS), there was a 45% reduction in the risk of disease progression or death in the trabectedin group compared with dacarbazine, (median PFS for trabectedin vs dacarbazine, 4.2 v 1.5 months; hazard ratio, 0.55; P<.001).  The interim analysis of overall survival (OS) (64%) censored) demonstrated a 13% reduction in risk of death in the trabectedin arm compared with dacarbazine (median OS for trabectedin vs dacarbazine, 12.4 v 12.9 months; hazard ration 0.8/; P=37).  Safety profiles were consistent with the well-characterized toxicities of both agents.  Trabectedin demonstrates superior disease control versus conventional dacarbazine in patients with advanced liposarcoma and leiomyosarcomas after a failure is experienced of prior chemotherapy.  
 
In another phase 3 pharmacokinetic study with trabectedin in patients with hepatic impairment (study #3007; NCT01343277 of trabectedin cs. dacarbazine in patients with advanced sarcomas and normal hepatic function.  In this study, the trabectedin group received 1.5 mg/m2 by 24 hour IV every 3 weeks until disease progression or unacceptable toxicity.  Following the trabectedin administration, 90% of patients had elevated ALT (32% grade 3-4) and 84% had elevated AST (17% grade 3-4). PFS was similar in patients with grade 3-4 hepatotoxity (n=109) versus grade 0-2 hepatotoxicity (n=231) (median [95% CI): 4.63 months versus 3.55 months.  This demonstrated that patient with HI that are treated with trabectedin, results in higher plasma exposures.  Hepatotoxicity in patients with normal liver functions can be addressed through dose reductions and delays.  
 
NCCN Soft Tissue Sarcoma guideline
Phase III data from a randomized, multicenter trial revealed a 2.7-month PFS benefit versus dacarbazine in metastatic LPS or LMS that progressed after anthracycline -based therapy and is ongoing to determine OS (Demetri GD, et al, 2016).  Another recent study supported the efficacy of trabectedin in translocation -related sarcoma. (Kawai A, et al, 2015) A phase III trial comparing trabectedin and doxorubicin-based chemotherapy revealed that neither arm showed superiority for PFS and OS; however, the study was underpowered.  (Blay JY, et al, 2014) Preliminary results from the randomized phase III T-SAR trial revealed a PFS benefit for trabectedin over best supportive care in both “L-type” (LPS and LMS) and non-L-type pretreated advanced sarcoma. However, trabectedin plus doxorubicin failed to demonstrate superiority over doxorubicin alone in a randomized phase II study of patients with advanced STS. (Martin-Broto J, et al. 2016) Trabectedin is included for palliative therapy as a category 1 recommendation for LPS and LMS (L-type and category 2A for non-L-type sarcomas.
 
2022 Update
Annual policy review completed with a literature search using the MEDLINE database through March 2022. No new literature was identified that would prompt a change in the coverage statement.

CPT/HCPCS:
J9352Injection, trabectedin, 0.1 mg

References: Blay JY, Leahy MG, Nguyen BB, et al.(2014) Randomised phase III trial of trabectedin versus doxorubicin-based chemotherapy as first-line therapy in translocation-related sarcomas. . Eur J Cancer. 2014 Apr;50(6):1137-47. doi: 10.1016/j.ejca.2014.01.012. Epub 2014 Feb 7.

Calvo E, Azaro A, Rodon J.(2017) Hepatic safety analysis of trabectedin: results of a pharmacokinetic study with trabectedin in patients with hepatic impairment and experience from a phase 3 clinical trial. Invest New Drugs. 2018 Jun;36(3):476-486. doi: 10.1007/s10637-017-0546-9. Epub 2017 Nov 27.

Demetri GD, von Mehren M, Jones R, et al.(2016) Efficacy and Safety of Trabectedin or Dacarbazine forMetastatic Liposarcoma or Leiomyosarcoma After Failure of Conventional Chemotherapy: Results of a Phase III Randomized Multicenter Clinical Trial. J Clin Oncol. 2016 Mar 10;34(8):786-93. doi: 10.1200/JCO.2015.62.4734. Epub 2015 Sep 14.

Kawai A, Araki N; Sugiura H, et al.(2015) Trabectedin monotherapy after standard chemotherapy versus best supportive care in patients with advanced, translocation-related sarcoma: a randomised, open-label, phase 2 study. . Lancet Oncol. 2015 Apr;16(4):406-16.doi: 10.1016/S1470-2045(15)70098-7. Epub 2015 Mar 18.

Martin-Broto J, Pousa AL, de las Peñas R, et al.(2016) Randomized Phase II Study of Trabectedin and Doxorubicin Compared With Doxorubicin Alone as First-Line Treatment in Patients With Advanced Soft Tissue Sarcomas: A Spanish Group for Research on Sarcoma Study. . J Clin Oncol. 2016 Jul 1;34(19):2294-302. doi: 10.1200/JCO.2015.65.3329. Epub 2016 May 16.

National Comprehensive Cancer Network Compendium®. Trabectedin. Last accessed 02/25/21. https://www.nccn.org/professionals/drug_compendium/content/

National Comprehensive Cancer Network. Soft Tissue Sarcoma (Version 1.2021). ). Last accessed 02/25/21. https://www.nccn.org/professionals/physician_gls/pdf/sarcoma_blocks.pdf

Yondelis® (trabectedin) [package insert]. Horsham, PA: Janssen Products, LP, 2015.


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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