In the Clinic provides overviews of novel oncology agents, addressing indications, mechanisms, administration recommendations, safety profiles, and other essential information needed for the appropriate clinical use of these drugs.
On October 23, 2015, trabectedin (Yondelis) was approved for the treatment of patients with unresectable or metastatic liposarcoma or leiomyosarcoma after a prior anthracycline-containing regimen.1,2
Supporting Efficacy Data
Approval of trabectedin was based on improvement in progression-free survival in an open-label phase III trial in which 518 anthracycline-pretreated patients were randomly assigned 2:1 to receive trabectedin at 1.5 mg/m2 as an intravenous infusion over 24 hours once every 3 weeks (n = 345) or dacarbazine at 1,000 mg/m2 as an intravenous infusion over 20 to 120 minutes once every 3 weeks (n = 173).3
The trial excluded patients with central nervous system metastasis, elevated serum bilirubin or significant chronic liver disease (eg, cirrhosis or active hepatitis), history of myocardial infarction within 6 months, history of New York Heart Association class II to IV heart failure, or abnormal left-ventricular ejection fraction. Patients randomized to the dacarbazine arm were not offered trabectedin at the time of disease progression.
Patients had a median age of 56 years (range = 17 to 81 years); 70% were female; 76% were white, 12% were black, and 4% were Asian; 73% had leiomyosarcoma and 27% had liposarcoma; 49% had Eastern Cooperative Oncology Group performance status of 0; and 89% had received at least two prior chemotherapy regimens. The most common prior drugs were doxorubicin (90%), gemcitabine (81%), docetaxel (74%), and ifosfamide (59%), with approximately 10% of patients having received pazopanib (Votrient).
Median investigator-determined progression-free survival was 4.2 months in the trabectedin group vs 1.5 months in the dacarbazine group (hazard ratio [HR] = 0.55, P < .001). Median overall survival was 13.7 vs 13.1 months (HR = 0.93, P = .49). Objective response rates were 7% vs 6%, with median durations of response of 6.9 vs 4.2 months.
How It Works
Trabectedin is an alkylating drug that binds guanine residues in the minor groove of DNA, forming adducts and resulting in a bending of the DNA helix toward the major groove. Adduct formation triggers events that can affect the subsequent activity of DNA-binding proteins, including some transcription factors, and DNA repair pathways, resulting in perturbation of the cell cycle and eventual cell death.
How It Is Used
The recommended dose of trabectedin is 1.5 mg/m2 via intravenous infusion over 24 hours through a central venous line every 21 days until disease progression or unacceptable toxicity in patients with normal bilirubin and aspartate aminotransferase (AST) or alanine aminotransferase (ALT) ≤ 2.5 times the upper limit of normal. There is no recommended dose of trabectedin in patients with serum bilirubin levels above the institutional upper limit of normal. Patients should be premedicated with intravenous dexamethasone (20 mg) 30 minutes prior to each dose.
Trabectedin should be permanently discontinued for persistent adverse reactions requiring a delay in dosing of more than 3 weeks, adverse reactions requiring further dose reduction following dose reduction to 1.0 mg/m2, and severe liver dysfunction indicated by bilirubin at least two times the upper limit of normal and AST or ALT at least three times the upper limit of normal with alkaline phosphatase (ALP) less than two times the upper limit of normal in the prior treatment cycle.
Treatment should be withheld for grade ≥ 2 neutropenia, severe or life-threatening increases in creatine phosphokinase, and left-ventricular dysfunction. Dose delay of up to 3 weeks is recommended for platelet count < 100,000/µL; absolute neutrophil count < 1,500/µL; total bilirubin greater than the upper limit of normal; AST, ALT, ALP, or creatine phosphokinase more than 2.5 times the upper limit of normal; decreased left-ventricular ejection fraction to less than the lower limit of normal or if there is clinical evidence of cardiomyopathy; and grade 3 or 4 nonhematologic adverse events.
Dose reduction is recommended for platelet count < 25,000/µL, absolute neutrophil count < 1,000/µL with fever/infection or < 500/µL lasting > 5 days, total bilirubin greater than the upper limit of normal, AST or ALT more than five times the upper limit of normal, ALP more than 2.5 times the upper limit of normal, creatine phosphokinase more than five times the upper limit of normal, decreased left-ventricular ejection fraction with absolute decrease of ≥ 10% and less than the lower limit of normal or if there is clinical evidence of cardiomyopathy, and grade 3 or 4 nonhematologic adverse events. The first dose reduction is to 1.2 mg/m2 every 3 weeks, and the second, is to 1.0 mg/m2 every 3 weeks.
Coadministration of strong CYP3A inhibitors (eg, ketoconazole, itraconazole, posaconazole, voriconazole, clarithromycin, telithromycin, indinavir, lopinavir, ritonavir, boceprevir, nelfinavir, saquinavir, telaprevir, nefazodone, conivaptan) and grapefruit/grapefruit juice should be avoided. If a strong CYP3A inhibitor for short-term use (< 14 days) must be used, it should be given 1 week after trabectedin infusion and discontinued the day prior to the next infusion. Coadministration of strong CYP3A inducers (eg, rifampin, phenobarbital, St. John’s wort) should be avoided.
In the phase III trial, the most common adverse events of any grade in the trabectedin group were nausea (75% vs 50% with dacarbazine), fatigue (69% vs 52%), vomiting (46% vs 22%), constipation (37% vs 31%), decreased appetite (37% vs 21%), and diarrhea (35% vs 23%). The most common grade 3 or 4 adverse events were fatigue (8% vs 1.7%), nausea (7% vs 1.7%), and vomiting (6% vs 1.2%). The most common grade 3 or 4 laboratory abnormalities were neutropenia (43% vs 26%), increased ALT (31% vs 0.6%), thrombocytopenia (21% vs 20%), and increased AST (17% vs 1.2%).
Adverse events led to dose reduction in 42% of patients in the trabectedin group, due to increased liver function tests in 24%, neutropenia in 8%, thrombocytopenia in 4.2%, fatigue in 3.7%, increased creatine phosphokinase in 2.4%, nausea in 1.1%, and vomiting in 1.1%, and to dose interruption in 52%, due to neutropenia in 31%, thrombocytopenia in 15%, increased liver function tests in 6%, fatigue in 2.9%, anemia in 2.6%, increased creatinine in 1.1%, and nausea in 1.1%. Adverse events led to permanent discontinuation of treatment in 26%, due to increased liver function tests in 5.6%, thrombocytopenia in 3.4%, fatigue in 1.6%, increased creatine phosphokinase in 1.1%, and decreased left-ventricular ejection fraction in 1.1%.
Trabectedin carries warnings/precautions for neutropenic sepsis, including fatal cases, rhabdomyolysis, hepatotoxicity, cardiomyopathy, including fatal cases, and embryofetal toxicity. Neutrophil counts and liver function tests should be monitored during treatment. The drug is contraindicated in patients with known hypersensitivity to trabectedin. Breastfeeding is not recommended in women receiving trabectedin. ■
1. U.S. Food and Drug Administration: Trabectedin. Available at www.fda.gov/Drugs/InformationOnDrugs/ApprovedDrugs/ucm468914.htm. Accessed November 4, 2015.
2. Yondelis® (trabectedin) for injection for intravenous use prescribing information, Janssen Products, LP, October 2015. Available at www.accessdata.fda.gov/drugsatfda_docs/label/2015/207953s000lbl.pdf. Accessed November 4, 2015.
3. 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. September 14, 2015 (early release online).