Yondelis (Trabectedin) Approved for the Treatment of Unresectable or Metastatic Soft-Tissue Sarcomas

March 2016, Vol 9, Seventh Annual Payers' Guide - Payers' Guide

Sarcomas, a group of malignant tumors that develop in soft tissue and bone, can affect any part of the body but most often occur in the abdomen, arms, and legs.1,2 Soft-tissue sarcomas typically form in the muscle, cartilage, fat, blood vessels, nerves, and other connective or supportive tissues, including the tendons and joint linings.1,2

An estimated 12,000 new cases of soft-tissue sarcomas were diagnosed in the United States in 2014, and 4700 people died from this disease.1 The incidence of soft-tissue sarcomas has been on the rise in the past 3 decades. Furthermore, the incidence of sarcomas is likely under­estimated, because sarcomas in the organs are difficult to distinguish from other malignancies.1

The proportion of patients affected by soft-tissue sarcomas is highest in individuals aged 55 to 64 years.3 Factors that may increase the risk for soft-tissue sarcoma include certain inherited disorders, exposure to chemicals (eg, herbicides, arsenic, dioxin), and exposure to radiation (eg, previous radiation treatment for other cancers).2

The overall 5-year relative survival rate is approximately 65% for patients with soft-tissue sarcoma.3 However, the 5-year relative survival is 15% for patients with distant metastatic soft-tissue sarcoma, and 22% for patients with regional metastatic disease (spread to regional lymph nodes).3 An estimated 40% to 50% of patients with soft-tissue sarcoma will progress to metastatic disease.4

The most common types of soft-tissue sarcomas include undifferentiated pleomorphic sarcoma, leiomyosarcoma, and liposarcoma.5 Leiomyosarcoma, the most common abdominal sarcoma, develops from smooth-muscle cells, and accounts for nearly 24% of all soft-tissue sarcomas.5,6 Liposarcoma arises in fat cells, and accounts for approximately 11.5% of all soft-tissue sarcomas.6 Other common types include gastrointestinal stromal tumors (GISTs), synovial sarcoma, and malignant peripheral nerve sheath tumors.7

Therapeutic options for soft-tissue sarcomas are based on the type, size, and location of the tumor; treatment may involve surgery, radiation therapy, chemotherapy, and targeted therapy.2

Initial therapy for unresectable soft-tissue sarcoma typically involves anthracycline-based chemotherapy (eg, doxorubicin) or gemcitabine-based chemotherapy.8 Targeted therapies for soft-tissue sarcomas include several US Food and Drug Administration (FDA)-approved anticancer drugs, as well as several investigational drugs currently in development.7,8

Overall, relatively few agents are available for soft-tissue sarcomas.2 Until recently, these agents included dactinomycin (for Ewing’s sarcoma and childhood rhabdomyosarcoma); doxorubicin hydrochloride (for metastatic soft-tissue sarcoma); doxorubicin hydrochloride liposome (for AIDS-related Kaposi’s sarcoma); imatinib mesylate (for the treatment of GIST and dermatofibrosarcoma protuberans); sunitinib malate (for GIST after disease progression or intolerance to imatinib mesylate); regorafenib (for GIST after previous treatment with imatinib mesylate or sunitinib malate); and pazopanib (for advanced soft-tissue sarcoma but not for liposarcoma or GIST).2,9-16

Trabectedin a New Option for Soft-Tissue Sarcoma

On October 23, 2015, trabectedin (Yondelis; Janssen), an alkylating drug, was approved by the FDA for the treatment of patients with unresectable or metastatic liposarcoma or patients with leiomyosarcoma who received a previous anthracycline-based regimen.17,18

Richard Pazdur, MD, Director of the FDA’s Office of Hematology and Oncology Products, stated, “The treatment of advanced or metastatic soft-tissue sarcoma represents a difficult challenge with few effective therapeutic choices available for patients. Today’s approval of Yondelis provides a treatment option for advanced or metastatic liposarcoma and leiomyosarcoma.”18

George D. Demetri, MD, Director, Ludwig Center at Harvard and Director, Center for Sarcoma and Bone Oncology, Dana-Farber Cancer Institute, and principal investigator of the pivotal phase 3 trabectedin study, said, “In the clinical trial, YONDELIS significantly increased progression free survival compared to dacarbazine; this is an important endpoint for these patients, in whom rapid worsening of the disease can lead to worse symptoms and life-threatening situations.”19

This new FDA indication for the treatment of liposarcoma and leiomyosarcoma makes trabectedin the first drug to receive FDA approval for the treatment of patients with liposarcoma in the United States.19

Mechanism of Action

Trabectedin is a marine-derived alkylating drug with a complex mechanism of action that affects cell biology processes in tumor cells.8,17 Trabectedin binds to the minor groove of DNA, forming adducts, and consequently bending the DNA helix toward the major groove of DNA. This adduct formation affects the subsequent function of DNA-binding proteins, including some transcription factors, and DNA repair processes, resulting in the disruption of the cell cycle and in eventual cell death.8,17

Dosage and Administration

The recommended dosage of trabectedin is 1.5 mg/m2 administered as an intravenous (IV) infusion for 24 hours through a central venous line every 21 days (3 weeks), until disease progression or until unacceptable toxicity, in patients with normal bilirubin levels and aspartate transaminase or alanine transaminase levels ≤2.5 times the upper limit of normal.17

There is no recommended dose of trabectedin for patients with serum bilirubin levels above the institutional upper limit of normal.17
Premedication with dexamethasone 20 mg is administered intravenously 30 minutes before each dose of trabectedin.17

Trabectedin is available as a 1-mg sterile lyophilized powder in a single-dose glass vial.17

Clinical Studies

The FDA approval of trabectedin was based on a randomized, open-label, active-controlled study (Study 1) that demonstrated its clinical efficacy and safety in patients with metastatic or recurrent leiomyosarcoma or liposarcoma.8,17 Study 1 compared trabectedin 1.5 mg/m2 as a 24-hour continuous IV infusion once every 3 weeks versus dacarbazine 1000 mg/m2 IV infusion (20-120 minutes) once every 3 weeks in patients with unresectable, locally advanced or metastatic leiomyosarcoma or liposarcoma who received previous treatment with an anthracycline-based regimen and 1 additional cytotoxic chemotherapy regimen.17

Patients received continued treatment with trabectedin or dacarbazine until disease progression or until unacceptable toxicity; patients in the trabectedin arm were required to receive an IV injection of dexamethasone 20 mg before each trabectedin infusion.17

The primary efficacy end points included investigator-assessed progression-free survival according to the Response Evaluation Criteria in Solid Tumors version 1.1, overall survival, objective response rate, and duration of response.17

Patients who received trabectedin in Study 1 showed a significant improvement in progression-free survival —a 45% reduction in the risk for disease progression or death compared with patients who received dacarbazine (Table).17 Furthermore, a subgroup analysis that included 60% of the total study population showed similar progression-free survival results as assessed by an independent radiology committee. The median overall survival was 13.7 months with trabectedin versus 13.1 months with dacarbazine, a nonsignificant difference.17

Figure 1

Adverse Events

Adverse reactions that occurred in ≥10% of patients who received trabectedin and at a higher incidence than in patients who received dacarbazine included fatigue (69%), decreased appetite (37%), peripheral edema (28%), dyspnea (25%), headache (25%), arthralgia (15%), myalgia (12%), and insomnia (15%).17 Other clinically notable adverse events that occurred in <10% of patients with soft-tissue sarcoma who received trabectedin included peripheral neuropathy, paresthesia, hypoesthesia, and pulmonary embolism.17

The most common (≥5%) grade 3 or 4 laboratory abnormalities associated with trabectedin therapy include neutropenia (43%), increased alanine transaminase levels (31%), thrombocytopenia (21%), anemia (19%), increased aspartate transaminase levels (17%), and increased creatine phosphokinase levels (6.4%).17

Overall, 26% (98 of 378) of patients in Study 1 permanently discontinued trabectedin treatment; the most common adverse events resulting in the discontinuation of trabectedin included increased liver tests (5.6%), thrombocytopenia (3.4%), fatigue (1.6%), increased creatine phosphokinase levels (1.1%), and decreased ejection fraction (1.1%).17


Trabectedin is contraindicated in patients with a known hypersensitivity to trabectedin.17

Drug Interactions

Patients taking trabectedin should avoid the concomitant use of strong cytochrome (CY) P3A inhibitors, as well as grapefruit or grapefruit juice. Patients taking trabectedin should also avoid the use of strong CYP3A inducers.17

Warnings and Precautions

Neutropenic sepsis. Severe, possibly fatal, neutropenic sepsis may occur with the use of trabectedin. Patients’ neutrophil count should be assessed before each dose of trabectedin and periodically throughout the treatment cycle. Trabectedin should be withheld in patients with grade ≥2 neutropenia.17

Rhabdomyolysis. Rhabdomyolysis and musculoskeletal toxicity can occur with trabectedin. Creatine phosphokinase levels should be assessed before each administration. Trabectedin should be withheld in patients with severe or life-threatening elevations in creatine phosphokinase levels.17

Hepatotoxicity. Hepatotoxicity, including hepatic failure, can occur with trabectedin. Patients’ liver function test should be assessed before each administration of trabectedin. Elevated liver function tests should be managed by delaying, interrupting, reducing, or permanently discontinuing trabectedin, depending on the severity and the duration of the liver function test results.17

Cardiomyopathy. Severe and fatal cardiomyopathy can occur with trabectedin therapy. Left-ventricular ejection fraction should be assessed before starting trabectedin therapy, and at 2- to 3-month intervals until trabectedin is discontinued. Trabectedin should be withheld in patients with left-ventricular dysfunction.17

Embryo-fetal toxicity. Based on its mechanism of action, trabectedin can cause fetal harm when used during pregnancy; therefore, pregnant women should be advised of the risk for fetal harm. Women of reproductive age should use contraception during treatment with trabectedin and for 2 months after the last dose. Because trabectedin may harm spermatozoa, possibly causing fetal or genetic abnormalities, men with a sexual partner of reproductive potential should use contraception during therapy with trabectedin, and for 5 months after the last dose of trabectedin.17

Use in Specific Populations

Lactation. Breast-feeding should be discontinued during treatment with trabectedin.17

Pregnancy. Data on the use of trabectedin during pregnancy are not available. Trabectedin can cause fetal harm when used during pregnancy.17

Females and males of reproductive potential. Women and men should be advised of the risk for decreased fertility with trabectedin therapy. Because trabectedin can cause fetal harm, contraception is recommended for women and men of reproductive potential.17

Pediatric use. The data are insufficient to establish the safety and effectiveness of trabectedin in pediatric patients.17

Geriatric use. There were insufficient numbers of patients aged ≥65 years in the trabectedin clinical trials to determine whether their treatment responses differed from those of younger patients.17

Hepatic impairment. There are insufficient data to evaluate trabectedin in patients with hepatic impairment.17

Renal impairment. Patients with mild or moderate renal impairment do not require a dose adjustment of trabectedin. Trabectedin was not evaluated in patients with severe renal impairment or with end-stage renal disease.17


The FDA approval of trabectedin represents the availability of a new treatment option for patients with liposarcomas or leiomyosarcomas—2 malignancies that account for 35% of all soft-tissue sarcoma cases.6,18 Trabectedin is indicated for the treatment of patients with unresectable or metastatic liposarcomas and leiomyosarcomas that were previously treated with an anthracycline-containing regimen. In a pivotal phase 3 study, treatment with trabectedin demonstrated a 45% reduction in the risk for disease progression or death compared with dacarbazine.


1. National Cancer Insitute. A snapshot of sarcoma. November 5, 2014. www.cancer.gov/research/progress/snapshots/sarcoma. Accessed October 30, 2015.
2. Mayo Clinic staff. Diseases and conditions: soft tissue sarcoma. July 1, 2015. www.mayoclinic.org/diseases-conditions/soft-tissue-sarcoma/basics/definition/con-20033386. Accessed October 30, 2015.
3. National Cancer Institute. SEER stat fact sheets: soft tissue including heart cancer. http://seer.cancer.gov/statfacts/html/soft.html. Accessed November 5, 2015.
4. Italiano A, Mathoulin-Pelissier S, Le Cesne A, et al. Trends in survival for patients with metastatic soft-tissue sarcoma. Cancer. 2011;117:1049-1054.
5. American Cancer Society. Sarcoma: adult soft tissue cancer. Revised March 16, 2015. www.cancer.org/cancer/sarcoma-adultsofttissuecancer/detailedguide/sarcoma-adult-soft-tissue-cancer-key-statistics. Accessed November 6, 2015.
6. Toro JR, Travis LB, Wu HJ, et al. Incidence patterns of soft tissue sarcomas, regardless of primary site, in the Surveillance, Epidemiology and End Results program, 1978-2001: an analysis of 26,758 cases. Int J Cancer. 2006;119:2922-2930.
7. National Comprehensive Cancer Network. NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines): soft tissue sarcoma. Version 1.2015. February 9, 2015. www.nccn.org/store/login/login.aspx?ReturnURL=http://www.nccn.org/pro fessionals/physician_gls/pdf/sarcoma.pdf. Accessed November 5, 2015.
8. Demetri GD, von Mehren M, Jones RL, et al. Efficacy and safety of trabectedin or dacarbazine for metastatic liposarcoma or leiomyosarcoma after failure of conventional chemotherapy: results of a phase III randomized multicenter clinical trial. J Clin Oncol. 2015 Sep 14. Epub ahead of print.
9. National Cancer Institute. Drugs approved for soft tissue sarcoma. Updated September 16, 2014. www.cancer.gov/about-cancer/treatment/drugs/soft-tissue-sarcoma. Accessed November 10, 2015.
10. Cosmegen (dactinomycin) injection [prescribing information]. Deerfield, IL: Ovation Pharmaceuticals Inc; March 2008.
11. Adriamycin (doxorubicin HCl) injection [prescribing information]. Bedford, OH: Bedford Laboratories; January 2014.
12. Doxil (doxorubicin hydrochloride liposome injection) [prescribing information]. Horsham, PA: Janssen Products, LP; April 2015.
13. Gleevec (imatinib mesylate) tablets [prescribing information]. East Hanover, NJ: Novartis; January 2015.
14. Sutent (sunitinib malate) capsules [prescribing information]. New York, NY: Pfizer Inc; April 2015.
15. Stivarga (regorafenib) tablets [prescribing information]. Whippany, NJ: Bayer HealthCare Pharmaceuticals Inc; April 2015.
16. Votrient (pazopanib) tablets [prescribing information]. Research Triangle Park, NC: GlaxoSmithKline; September 2015.
17. Yondelis (trabectedin) for injection [prescribing information]. Horsham, PA: Janssen Products, LP; October 2015.
18. US Food and Drug Administration. FDA approves new therapy for certain types of advanced soft tissue sarcoma. Press release. October 23, 2015. www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm468832.htm. Accessed October 30, 2015.
19. Janssen. U.S. FDA approves Yondelis (trabectedin) for the treatment of patients with unresectable or metastatic liposarcoma or leiomyosarcoma, two common subtypes of soft tissue sarcoma. Press release. October 23, 2015. www.janssen.com/us-fda-approves-yondelis-trabectedin-treatment-patients-unresectable-or-metastatic-liposarcoma-or. Accessed November 4, 2015.

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