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INDEX:
A B C D E F G H I J K L M N O P Q R S T U V W X Y Z

Effective Date: 07/01/2016 Title: Yondelis (Trabectedin)
Revision Date: 01/01/2017 Document: BI513:00
CPT Code(s): J9352
Public Statement

Effective Date:

a)    This policy will apply to all services performed on or after the above revision date which will become the new effective date.

b)    For all services referred to in this policy that were performed before the revision date, contact customer service for the rules that would apply.

1)    Yondelis (trabectedin) requires prior authorization.

2)    Yondelis is used to treat Liposarcoma and Leiomyosarcoma.

3)    Yondelis is considered a specialty drug and is covered under the medical benefit.


Medical Statement

Yondelis (trabectiedin) is considered medically necessary for patients who meet the following criteria:

1)    Diagnosis of unresectable or metastatic Liposarcoma or Leiomyosarcoma AND

2)    Have received a previous anthracycline-containing regimen.

 

Yondelis is considered experimental and investigational for the following indications (not an all-inclusive list):

§  Biliary tract carcinoma/cholangiocarcinoma

§  Breast cancer

§  Desmoplastic small round cell tumor

§  Fallopian tube cancer

§  Lung cancer (including non-small cell lung cancer)

§  Malignant solitary fibrous tumor

§  Melanoma

§  Meningioma

§  Mesothelioma

§  Osteosarcoma

§  Ovarian cancer

§  Pediatric sarcomas (including Ewing sarcoma, rhabdomyosarcoma, and spindle cell sarcoma)

§  Primary peritoneal cancer

§  Prostate cancer

§  Rhabdomyosarcoma

§  Small round cell sarcoma

§  Translocation-related sarcoma (including alveolar soft part sarcoma, clear cell sarcoma, endometrial stromal sarcoma, myxoid-round cell Liposarcoma, and synovial sarcoma


Background

Doxorubicin, ifosfamide and decarbonize have been long used in the treatment of uterine Leiomyosarcoma.  Novel active agents are represented by aromatase inhibitors, docetaxel, gemcitabine, pazopanib, and trabectedin (also known as ecteinascidin 743, ET-743, and NSC 684766).  Trabectedin is a marine-derived tetrahydroisoquinoline alkaloid.  It is originally derived from the Caribbean tunicate Ecteinascidia turbinata and is currently produced synthetically.  Trabectedin interacts with the minor groove of DNA and alkylates guanine at the N2 position, which bends towards the major groove.  It is believed that trabectedin affects various transcription factors involved in cell proliferation, especially via the transcription-coupled nucleotide excision repair system.  The drug blocks the cell cycle at the G (2) phase, while cells at the G (1) phase are most sensitive to the drug.  It also inhibits over-expression of the multi-drug resistance-1 (MDR-1) gene coding for the P-glycoprotein that is a major factor responsible for cells developing resistance to cancer drugs. 

 

Liposarcoma and Leiomyosarcoma: In a phase II, open-label, multi-center, randomized clinical trial, Demetri and colleagues (2009) evaluated the safety and effectiveness of trabectedin in adult patients with unresectable/metastatic Liposarcoma or Leiomyosarcoma after failure of prior conventional chemotherapy including anthracyclines and ifosfamide.  Patients were randomly assigned to one of two trabectedin regimens (via central venous access): 1.5 mg/m (2) 24-hour intravenous infusion once every 3 weeks (q3 week’s 24-hour) versus 0.58 mg/m (2) 3-hour intravenous (IV) infusion every week for 3 weeks of a 4-week cycle (qwk 3-hour).  Time to progression (TTP) was the primary efficacy end-point, based on confirmed independent review of images.  A total of 270 patients were randomly assigned; 136 (q3 weeks 24-hour) versus 134 (qwk 3-hour).  Median TTP was 3.7 months versus 2.3 months (hazard ratio [HR], 0.734; 95 % confidence interval [CI]: 0.554 to 0.974; p = 0.0302), favoring the q3 weeks 24-hour arm.  Median progression-free survival (PFS) was 3.3 months versus 2.3 months (HR, 0.755; 95 % CI: 0.574 to 0.992; p = 0.0418).  Median overall survival (OS; n = 235 events) was 13.9 months versus 11.8 months (HR, 0.843; 95 % CI: 0.653 to 1.090; p = 0.1920).  Although somewhat more neutropenia, elevations in aspartate transaminase (AST) / alanine transaminase (ALT), emesis, and fatigue occurred in the q3 weeks 24-hour, this regimen was reasonably well-tolerated.  Febrile neutropenia was rare (0.8 %).  No cumulative toxicities were noted.  The authors concluded that prior studies showed clinical benefit with trabectedin in patients with sarcomas after failure of standard chemotherapy.  This trial documented superior disease control with the q3 week’s 24-hour trabectedin regimen in Liposarcoma and Leiomyosarcoma, although the qwk 3-hour regimen also demonstrated activity relative to historical comparisons.  They stated that trabectedin may now be considered an important new option to control advanced sarcomas in patients after failure of available standard-of-care therapies.

 

The National Institute for Health and Clinical Excellence’s clinical guideline on “Trabectedin for the treatment of advanced soft tissue sarcoma” (NICE, 2010) stated that trabectedin is recommended as a treatment option for people with advanced soft tissue sarcoma (STS) if treatment with anthracyclines and ifosfamide has failed or they are intolerant of or have contraindications for treatment with anthracyclines and ifosfamide.

 

The Alberta Provincial Gynecologic Oncology Team’s clinical guideline on “Uterine sarcoma” (2013) noted that agents that have been used for palliative chemotherapy include cisplatin, decarbonize, docetaxel, doxorubicin, gemcitabine, ifosfamide, and trabectedin.

 

In a randomized, multi-center, prospective, dose-selection, phase IIb superiority trial, Bui-Nguyen et al (2015) examined if trabectedin as first-line chemotherapy for advanced/metastatic STS prolongs PFS, and selected the most appropriate trabectedin treatment schedule (3-hour or 24-hour infusion) in terms of safety, convenience and efficacy.  A total of 133 patients were randomized between doxorubicin (n = 43), trabectedin (3-hour infusion, T3h) (n = 47) and trabectedin (24-hour infusion, T24h) (n = 43).  Progression-free survival was defined as time from random assignment until objective progression by Response Evaluation Criteria in Solid Tumors (RECIST 1.1), a global deterioration of the health status requiring discontinuation of the treatment, or death from any cause.  The study was terminated due to lack of superiority in both trabectedin treatment arms as compared to the doxorubicin control arm.  Median PFS was 2.8 months in the T3h arm, 3.1 months in the T24h arm and 5.5 months in the doxorubicin arm.  No significant improvements in PFS were observed in the trabectedin arms as compared to the doxorubicin arm (T24h versus doxorubicin: HR of 1.13, 95 % CI: 0.67 to 1.90, p = 0.675; T3h versus doxorubicin: HR of 1.50, 95 % CI: 0.91 to 2.48, p = 0.944).  Only 1 toxic death occurred in the T3h arm, but treatment had to be stopped due to toxicity in 7 (15.2 %) (T3h), 8 (19.5 %) (T24h) and 1 (2.5 %) doxorubicin patients.  The authors concluded that doxorubicin continues to be the standard treatment in eligible patients with advanced/metastatic STS.  They stated that trabectedin 1.5 mg/m (2)/24-hour infusion is the overall proven approach to delivering this agent in the second-line setting for patients with advanced or metastatic STS.

 

In a multi-center, phase III clinical trial, Demetri et al (2015) compared trabectedin versus decarbonize in patients with advanced Liposarcoma or Leiomyosarcoma after prior therapy with an anthracycline and at least 1 additional systemic regimen.  Patients were randomly assigned in a 2:1 ratio to receive trabectedin or decarbonize intravenously every 3 weeks.  The primary end-point was OS, secondary end-points were disease control-PFS, TTP, objective response rate (ORR), and duration of response as well as safety and patient-reported symptom scoring.  A total of 518 patients were enrolled and randomly assigned to either trabectedin (n = 345) or decarbonize (n = 173).  In the final analysis of PFS, trabectedin administration resulted in a 45 % reduction in the risk of disease progression or death compared with decarbonize (median PFS for trabectedin versus decarbonize, 4.2 versus 1.5 months; HR of 0.55; p < 0.001); benefits were observed across all pre-planned subgroup analyses.  The interim analysis of OS (64 % censored) demonstrated a 13 % reduction in risk of death in the trabectedin arm compared with decarbonize (median OS for trabectedin versus decarbonize, 12.4 versus 12.9 months; HR of 0.87; p = 0.37).  The safety profiles were consistent with the well-characterized toxicities of both agents, and the most common grade 3 to 4 adverse effects were myelosuppression and transient elevation of transaminases in the trabectedin arm.  The authors concluded that trabectedin demonstrated superior disease control versus conventional decarbonize in patients who have advanced Liposarcoma and Leiomyosarcoma after they experienced failure of prior chemotherapy.  Because disease control in advanced sarcomas is a clinically relevant end-point, this study supported the activity of trabectedin for patients with these malignancies.

On October 23, 2015, the Food and Drug Administration (FDA) approved trabectedin (Yondelis) for the treatment of specific STSs (Liposarcoma and Leiomyosarcoma) that are unresectable or are metastatic.  This treatment is approved for patients who previously received chemotherapy that contained anthracycline.  The safety and effectiveness of Yondelis were demonstrated in 518 patients with metastatic or recurrent Leiomyosarcoma or Liposarcoma.  Subjects were randomly assigned to receive either Yondelis (n = 345) or decarbonize (n = 173), another chemotherapy drug.  Participants who received Yondelis experienced a delay in the growth of their tumor (PFS), which occurred on average about 4.2 months after starting treatment, compared to participants assigned to decarbonize, whose disease progressed an average of 1.5 months after starting treatment.  The most common side effects among participants who received Yondelis were nausea, fatigue, vomiting, diarrhea, constipation, decreased appetite, dyspnea, headache, peripheral edema, neutropenia, thrombocytopenia, anemia, elevated liver enzymes and decreases in albumin.  Yondelis carries a warning alerting health care providers of the risk of severe and fatal neutropenic sepsis, rhabdomyolysis, hepatotoxicity, extravasation, tissue necrosis and cardiomyopathy.  Health care providers are also encouraged to advise women of potential risks to a developing fetus when taking Yondelis.  Women who are taking Yondelis should not breast-feed.

Trabectedin has also been studied for the treatment of various types of cancers.  In particular, trabectedin has completed phase II studies for rhabdomyosarcoma and small round cell sarcoma, which are aggressive tumors that occur predominantly in children (No authors listed, 2006).

Biliary Tract Carcinoma/Cholangiocarcinoma: In a phase I, open-label, dose-finding study, Gore et al (2012) determined the maximum tolerated dose (MTD), safety and pharmacokinetics of trabectedin with capecitabine in patients with advanced malignancies.  Patients refractory to standard therapy received trabectedin (3-h IV infusion, 0.4 to 1.3 mg/m (2), day 1) and capecitabine (2,000 or 1,600 mg/m (2)/day orally, days 2 to 15) every 3 weeks.  Standard "3 + 3" dose escalation was used to define the MTD.  Anti-tumor response was assessed every 2 cycles; adverse events (AEs) were recorded throughout.  A total of 40 patients received 149 cycles of treatment (median 2; range of 1 to 11) at 9 dose levels.  Gastro-intestinal dose-limiting toxicities in 2 patients at 2 dose levels with capecitabine at 2,000 mg/m(2)/day prompted dose reduction to 1,600 mg/m(2)/day and initiation of new trabectedin dose escalation at 0.6 mg/m(2).  The MTD was capecitabine 1,600 mg/m (2)/day + trabectedin 1.1 mg/m (2).  Common grade 3 to 4 drug-related AEs were neutropenia (20 %), nausea (18 %), diarrhea (15 %) and palmar-plantar erythrodysesthesia (15 %).  One patient with cholangiocarcinoma achieved a sustained partial response (PR), and 18 patients maintained stable disease (SD) (6 for greater than or equal to 6 months).  The authors concluded that the combination of trabectedin and capecitabine was generally well-tolerated, without pharmacokinetic interactions, and showed some activity in patients with advanced cancers.

Peraldo-Neia et al (2014) evaluated the mechanism of action of ET-743 in pre-clinical models of biliary tract carcinoma (BTC).  Six BTC cell lines (TFK-1, EGI-1, TGBC1, WITT, KMCH, and HuH28), 2 primary cell cultures derived from BTC patients (the EGI-1 and a new established BTC patient-derived xenografts) were used as pre-clinical models to investigate the anti-tumor activity of ET-743 in-vitro and in-vivo.  Gene expression profiling was also analyzed upon ET-743 treatment in in-vivo models.  These researchers found that ET-743 inhibited cell growth of BTC cell lines and primary cultures (IC50 [the concentration of an inhibitor where the response (or binding) is reduced by 50 %] ranging from 0.37 to 3.08 nM) preferentially inducing apoptosis and activation of the complex DNA damage-repair proteins (p-ATM, p-p53 and p-Histone H2A.x) in-vitro.  In EGI-1 and patient-derived xenografts, ET-743 induced tumor growth delay and reduction of vasculogenesis.  In-vivo, ET-743 induced a deregulation of genes involved in cell adhesion, stress-related response, and in pathways involved in cholangiocarcinogenesis, such as the IL-6, Sonic Hedgehog and Wnt signaling pathways.  The authors concluded that these results suggested that ET-743 could represent an alternative chemotherapy for BTC treatment and encouraged the development of clinical trials in BTC patients resistant to standard chemotherapy.

Breast Cancer: Atmaca and colleagues (2013) examined if trabectedin mediated apoptosis shows any diversity in human breast cancer cell lines with different genotypes.  Trabectedin induced cytotoxicity and apoptosis in both breast cancer cells in a time- and concentration-dependent manner.  The expression levels of the death receptor pathway molecules, TRAIL-R1/DR4, TRAIL-R2/DR5, FAS/TNFRSF6, TNF RI/TNFRSF1A, and FADD were significantly increased by 2.6-, 3.1-, 1.7-, 11.2- and 4.0-fold by trabectedin treatment in MCF-7 cells.  However, in MDA-MB-453 cells, the mitochondrial pathway related pro-apoptotic proteins Bax, Bad, Cytochrome c, Smac/DIABLO, and Cleaved Caspase-3 expressions were induced by 4.2-, 3.6-, 4.8-, 4.5-, and 4.4-fold, and the expression levels of anti-apoptotic proteins Bcl-2 and Bcl-XL were reduced by 4.8- and 5.2-fold in MDA-MB-453 cells.  Moreover, trabectedin treatment increased the generation of reactive oxygen species (ROS) in both breast cancer cells.  The authors concluded that trabectedin resulted in selective activation of extrinsic and intrinsic apoptotic pathways in 2 genotypically different breast cancer cells.  They stated that these preliminary data might guide clinicians to choose appropriate combination agents with trabectedin based on different molecular subtypes of breast cancer.

In an open-label, multi-center, randomized, phase II study, Goldstein and associates (2014) evaluated the safety and effectiveness of trabectedin for breast cancer.  Women with advanced breast cancer previously treated with less than or equal to 2 lines of chemotherapy for advanced disease, including both anthracyclines and taxanes, were randomized (1:1) to 3-hour infusions of trabectedin 1.3 mg/m (2) once every 3 weeks (1/3 treatment arm) or 0.58 mg/m (2) every week for 3 of 4 weeks (3/4 treatment arm).  The primary end-point was objective response; secondary end-points included TTP, PFS, and OS.  A total of 52 women (median age of 50 years; median chemotherapy agents of 4) were enrolled.  Relative trabectedin dose intensities were 81 % and 76 % in the 1/3 and 3/4 treatment arms, respectively.  Objective response rates were 12 % (3 of 25) and 4 % (1 of 27), respectively.  Stable disease was observed in 14 (56 %) and 11 (41 %) patients in the 1/3 and 3/4 treatment arms, respectively, with median durations of 3.5 and 3.7 months.  Median TTP and PFS were higher in the 1/3 treatment arm (3.1 months each) than in the 3/4 treatment arm (2.0 months each).  At a median follow-up of 7 months in both treatment arms, median OS was not reached in the 1/3 treatment arm and was 9.4 months in the 3/4 treatment arm.  The most frequent drug-related adverse events in the 1/3 and 3/4 treatment arms, respectively, were ALT level increases (68 % versus 63 %), nausea (56 % versus 59 %), and asthenia (56 % versus 48 %).  Neutropenia and increases in ALT levels were the most frequent grade 3/4 events.  Both types of events were usually transient and reversible.  The authors concluded that in the population studied, trabectedin showed a manageable safety profile for both regimens analyzed.  There were higher ORR and a longer PFS in the 1/3 treatment arm compared with the 3/4 treatment arm.  These preliminary findings need to be validated in well-designed phase III clinical trials.

Furthermore, National Comprehensive Cancer Network (NCCN)’s clinical practice guideline on “Breast cancer” (Version 3.2015) does not mention trabectedin as a therapeutic option.

Desmoplastic Small Round Cell Tumor: Brunetti et al (2014) stated that desmoplastic small round cell tumor (DSRCT) is a rare and aggressive cancer that usually develops in the peritoneal cavity of young males.  Its prognosis is dismal; current therapeutic options include the combination of multi-agent chemotherapy, aggressive surgery, radiation therapy, autologous stem cell transplantation, and hyperthermic intraperitoneal chemotherapy (HIPEC).  These investigators reported the administration of trabectedin in a patient with DSRCT, heavily pre-treated with conventional multi-agent chemotherapy, HIPEC, and surgery.  The patient achieved a prolonged PR and an extended period of SD with third-line trabectedin, following disease progression after conventional multi-agent chemotherapy, HIPEC, and surgery.  The authors concluded that trabectedin may be a therapeutic option in multi-modal therapy for the management of DSRCT and warrants further research to explore the impact of trabectedin in the treatment of this disease.

Frezza et al (2014) reported 2 cases of metastatic, pre-treated DSRCT patients achieving SD with trabectedin.  Two males aged 19 and 23 years were treated with trabectedin, 1.5 mg/m (2) over 24 hours 3 weekly for 6 and 5 cycles, respectively.  Best responses were SD in patient 1 and PR (RECIST 1.1) in patient 2; PFS was 4 months in both cases.  The authors concluded that the findings of this study supported that trabectedin is safe and active in pre-treated DSRCT patients.  They stated that further prospective and collaborative efforts are needed to better define its role in the management of this disease.

Malignant Solitary Fibrous Tumor: Chaigneau et al (2011) noted that solitary fibrous tumors (SFTs) are rare and have an unpredictable course.  Local recurrence rate varies between 9 and 19 %, and rate of metastatic involvement between 0 and 36 %.  Solitary fibrous tumors are characterized by a typical architecture and immuno-histochemistry tests.  The most important prognostic factor is the complete resection of primary tumor.  Treatment of recurrences is not clearly established.  If a SFT is too advanced to allow surgical resection, radiotherapy and chemotherapy may be used.  The most often used drugs are doxorubicin and/or ifosfamide.  These investigators reported the case of a man with metastatic SFT treated with trabectedin, administered at a dose of 1.5 mg/ m (2) every 3 weeks.  After 3 cycles, metastases had significantly decreased.  Recurrence of the disease was reported 8 months after the start of trabectedin.  The authors concluded that this case showed that trabectedin is a possible therapeutic option.

Khalifa et al (2015) stated that several therapeutic options have been reported for the treatment of SFTs, but with uncertain rates of efficacy.  In a retrospective, multi-center study, these researchers described the activity of trabectedin in a series of patients with SFTs.  Trabectedin was administered at an initial dose of 1.5 mg/m (2), q3 weeks.  The best tumor response was assessed according to the RECIST 1.1.  The Kaplan-Meier method was used to estimate median PFS and OS.  The growth-modulation index (GMI) was defined as the ratio between the TTP with trabectedin (TTPn) and the TTP with the immediately prior line of treatment (TTPn-1).  A total of 11 patients treated with trabectedin for advanced SFT were identified.  Trabectedin had been used as second-line treatment in 8 patients (72.7 %) and as at least third-line therapy in a further 3 (27.3 %).  The best RECIST response was a PR in 1 patient (9.1 %) and SD in 8 patients (72.7 %).  Disease-control rate (DCR = PR + SD) was 81.8 %.  After a median follow-up of 29.2 months, the median PFS was 11.6 months (95 % CI: 2.0 to 15.2 months) and the median OS was 22.3 months (95 % CI: 9.1 months to not reached).  The median GMI was 1.49 (range of 0.11 to 4.12).  The authors concluded that trabectedin is a very promising treatment for advanced SFTs; further investigations are needed.

Meningioma: Preusser et al (2013) stated that surgical resection and radiotherapy are regarded as standard of care for the treatment of high-grade meningiomas.  In the recurrent setting after exhaustion of all local therapeutic options, no effective treatments are known and several drugs have failed to show efficacy, but novel compounds may offer hope for better disease control.  Up-regulation of pro-angiogenic molecules and dysregulation of some signaling pathways such as the platelet-derived growth factor (PDGF) and mammalian target of rapamycin (mTOR) are recurrently found in high-grade meningiomas.  Furthermore, in-vitro studies and single patient experience indicated that trabectedin may be an effective therapy in the treatment of meningioma.  Unfortunately, so far there is a lack of conclusive clinical trials to draw definite conclusions of efficacy of these approaches.  The authors concluded that there remains a significant unmet need for defining the role of medical therapy in recurrent high-grade meningioma, and more basic research and multi-centric well-designed trials are needed in this rare and devastating tumor type.  Potentially promising novel therapeutics included anti-angiogenic drugs, molecular inhibitors of signaling cascades, immunotherapeutic and trabectedin; however, more basic research is needed to identify more promising drug targets.

Mesothelioma: Ceriani and colleagues (2015) noted that trabectedin is an anti-cancer agent registered for the second-line treatment of STS.  No pre-clinical data are available on its tumor distribution, so a method for quantification in neoplastic tissues is needed.  These researchers validated an LC-MS/MS assay determining the recovery, sensitivity, linearity, precision and accuracy in mouse tumor and liver samples.  The limit of quantification was 0.10 ng/ml with a curve range of 0.10 to 3.00 ng/ml (accuracy 96.1 to 102.1 %); and inter-day precision and accuracy of quality control samples (QCs) were 6.0 to 8.2 and 97.0 to 102.6 %, respectively.  The method was applied in mesothelioma xenografts treated with therapeutic doses.  The authors concluded that the method was validated for measuring trabectedin in tissues.  In a mesothelioma xenograft model, trabectedin distributed preferentially in tumor compared with liver.  The role of trabectedin in the treatment of mesothelioma has to be further investigated.

Non-Small Cell Lung Cancer: Massuti and colleagues (2012) noted that previous studies in sarcoma found that a composite gene signature, including high expression of nucleotide excision repair (NER) genes (XPG and/or ERCC1) and low expression of homologous recombination repair (HR) genes (BRCA1), identifies a highly sensitive population of patients with significantly improved outcome to trabectedin.  In an exploratory phase II trial, these researchers evaluated a customized trabectedin treatment according to this gene signature in patients with non-small cell lung cancer (NSCLC) after the failure of standard platinum-based treatment.  Patients were selected according to their mRNA expression (elevated XPG and/or ERCC1, with low BRCA1) using the following values as cut-off: XPG = 0.99, ERCC1 = 3.47 and BRCA1 = 12.00.  Trabectedin was administered as a 1.3 mg/m (2) 3-hour IV infusion every 3 weeks (q3wk).  The primary efficacy end-point was the PFS rate at 3 months.  Objective response according to the RECIST was a secondary efficacy end-point.  Two of 18 evaluable patients (11.1 %; 95 % CI: 1.38 to 34.7 %) achieved PFS rate at 3 months.  The primary efficacy objective (at least 3 of 18 patients being progression-free at 3 months) was not met, and therefore the trial was terminated early.  No objective responses per RECIST were achieved; 4 patients had SD.  Median PFS was 1.3 months, and median OS was 5.9 months.  Trabectedin was usually well-tolerated, with a safety profile similar to that described in patients with other tumor types.  The authors concluded that customized treatment with trabectedin 1.3 mg/m (2) 3-h q3wk according to composite gene signature (XPG and/or ERCC1 over-expression, and BRCA1 under-expression) was well-tolerated, but had modest activity in NSCLC patients pre-treated with platinum.  They stated that further clinical trials with trabectedin as single-agent in this indication are not warranted.

Osteosarcoma: Gastaud et al (2013) noted that treatment of osteosarcoma of the extremities consists of surgical resection preceded and followed by chemotherapy, including high-dose methotrexate or Adriamycin-based protocols.  When distant relapse occurs, therapeutic options are scarce.  Trabectedin has been employed for the treatment of patients with advanced STS after failure of anthracyclines and ifosfamide.  In this indication, the 6-month PFS is about 35 to 40 %.  Recent reports showed that some specific single nucleotide polymorphisms (SNPs) from DNA repair genes could be associated with sensitivity to trabectedin in STSs.  These researchers reported their experience of 2 metastatic, heavily pre-treated osteosarcoma patients who were treated with trabectedin.  Pyro-sequencing analyses of tumors from both patients for several SNPs of the ERCC1, ERCC5 and BRAC1 genes were performed.  Both patients showed major response to trabectedin, which was interestingly related with homozygosity of the common guanine allele of ERCC5 (G/G genotype; Asp/Asp) after pyro-sequencing analysis of tumors from both patients.  This polymorphism was previously shown to be associated with better outcome in STS patients treated with trabectedin.  The authors concluded that homozygosity for the wild-type Asp1104 SNP of the ERCC5 gene was found in 2 cases of relapsed osteosarcoma, who responded to trabectedin.  The role of trabectedin in the treatment of osteosarcoma needs to be validated in well-designed studies.

Ovarian Cancer: In a phase II clinical trial, Monk et al (2011) estimated the activity of docetaxel 60 mg/m(2) IV over 1 hour followed by trabectedin 1.1 mg/m(2) over 3 hours with filgrastim, pegfilgrastim, or Sargramostim every 3 weeks (1 cycle).  Patients with recurrent and measurable disease, acceptable organ function, performance status (PS) less than or equal to 2, and less than or equal to 3 prior regimens were eligible.  A 2-stage design was utilized with a target sample size of 35 subjects per stage.  Another Gynecologic Oncology Group study within the same protocol queue involving a single agent taxanes showed a response rate (RR) of 16 % (90 % CI: 8.6 to 28.5 %) and served as a historical control for direct comparison.  The present study was designed to determine if the current regimen had an RR of greater than or equal to 36 % with 90 % power.  A total of 71 patients were eligible and evaluable (prior regimens: 1 = 28 %, 2 = 52 %, and 3 = 20 %).  The median number of cycles was 6 (438 total cycles, range of 1 to 22).  The number of patients responding was 21 (30 %; 90 % CI: 21 to 40 %).  The odds ratio for responding was 2.2 (90 % 1-sided CI: 1.07 to infinity).  The median PFS and OS were 4.5 months and 16.9 months, respectively.  The median response duration was 6.2 months. Numbers of subjects with grade 3/4 toxicity included neutropenia 7/14; constitutional 8/0; GI (excluding nausea/vomiting) 11/0; metabolic 9/1; and pain 6/0.  There were no treatment-related deaths, nor cases of liver failure.  The authors concluded that this combination was well-tolerated and appeared more active than the historical control of single agent taxanes therapy in those with recurrent ovarian and peritoneal cancer after failing multiple lines of chemotherapy; they stated that further study is needed.

Cancer Care Ontario Gynecologic Cancer Disease Site Group’s clinical guideline on “Optimal chemotherapy for recurrent ovarian cancer” (Fung et al, 2011) stated that “A 672 patient study, OVA-301, compared PEGylated liposomal doxorubicin (PLD) to trabectedin-PLD, and found a statistically significantly improved PFS with the combination (7.3 versus 5.8 months, p = 0.019).  Despite this finding, which implies the viability of the combination as a treatment option, the trabectedin-PLD combination is not recommended at this time, based on the finding of no differences in quality of life (QOL) or OS, and the lack of clinical significance of a 6-week PFS difference”.

Up-to-date reviews on “First-line chemotherapy for advanced (stage III or IV) epithelial ovarian, fallopian tubal, and peritoneal cancer” (Herzog and Armstrong, 2015) and “Medical treatment for relapsed epithelial ovarian, fallopian tubal, or peritoneal cancer: Platinum-resistant disease” (Birrer and Fujiwara, 2015) do not mention trabectedin as a therapeutic option.

Furthermore, NCCN’s clinical practice guideline on “Ovarian cancer including fallopian tube cancer and primary peritoneal cancer” (Version 2.2015) does not mention trabectedin as a therapeutic option.

Pediatric Sarcomas: Baruchel et al (2012) determined the toxicity, effectiveness and pharmacokinetics of trabectedin given over 24 hours every 3 weeks to children with recurrent Ewing sarcoma, rhabdomyosarcoma, or non-rhabdomyosarcoma STSs.  Trabectedin was administered as a 24-hour IV infusion every 21 days.  Two dose levels were evaluated (1.3 and 1.5 mg/m (2)) for safety; effectiveness was then evaluated using a traditional 2-stage design (10+10) at the 1.5 mg/m (2) dose level.  Pharmacokinetics (day 1 and steady state) were performed during cycle 1.  A total of 50 patients were enrolled, 8 patients at 1.3 mg/m (2) and 42 at 1.5 mg/m (2).  Dose limiting toxicities (DLTs) in the dose finding component included fatigue and reversible gamma glutamyl transferase (GGT) elevation in 1/6 evaluable patients at 1.3 mg/m(2) and 0/5 at 1.5 mg/m(2).  Effectiveness was evaluated in 42 patients enrolled at the 1.5 mg/m(2) dose of whom 22 % experienced reversible grade 3 or 4 toxicities that included AST, ALT, or GGT elevations, myelosuppression and deep venous thrombosis.  One patient with rhabdomyosarcoma had a PR and 1 patient each with rhabdomyosarcoma, spindle cell sarcoma and Ewing sarcoma (ES) had SD for 2, 3 and 15 cycles, respectively.  The authors concluded that trabectedin is safe when administered over 24 hours at 1.5 mg/m (2).  They stated that trabectedin did not demonstrate sufficient activity as a single agent for children with relapsed pediatric sarcomas.

Ordonez et al (2015) noted that recent pre-clinical evidence has suggested that ES bearing EWSR1-ETS fusions could be particularly sensitive to poly ADP ribose polymerase inhibitors (PARPinh) in combination with DNA damage repair (DDR) agents.  Trabectedin is an anti-tumoral agent that modulates EWSR1-FLI1 transcriptional functions, causing DNA damage.  Interestingly, PARP1 is also a transcriptional regulator of EWSR1-FLI1, and PARPinh disrupts the DDR machinery.  Thus, given the impact and apparent specificity of both agents with regard to the DNA damage/DDR system and EWSR1-FLI1 activity in ES, these researchers examined the activity of combining PARPinh and trabectedin in in-vitro and in-vivo experiments.  The combination of olaparib and trabectedin was found to be highly synergistic, inhibiting cell proliferation, inducing apoptosis and the accumulation of G2/M.  The drug combination also enhanced γH2AX intra-nuclear accumulation as a result of DNA damage induction, DNA fragmentation and global DDR deregulation, while EWSR1-FLI1 target expression remained unaffected.  The effect of the drug combination was corroborated in a mouse xenograft model of ES and, more importantly, in 2 ES patient-derived xenograft (PDX) models in which the tumors showed complete regression.  The authors concluded that the combination of the 2 agents led to a biologically significant deregulation of the DDR machinery that elicited relevant anti-tumor activity in pre-clinical models and might represent a promising therapeutic tool that should be further explored for translation to the clinical setting.

Prostate Cancer: In a multi-center, phase II clinical trial, Michaelson and colleagues (2012) evaluated the safety and effectiveness of trabectedin in metastatic castration-resistant prostate cancer (CRPC).  Two schedules were evaluated in 3 cohorts: weekly as 3-hour IV infusion at 0.58 mg/m (2) for 3 out of 4 weeks (Cohort A, n = 33), and every 3 weeks (q3wk) as 24-hour IV infusion at 1.5 mg/m (2) (Cohort B1, n = 5) and 1.2 mg/m (2) (Cohort B2, n = 20).  The primary end-point was prostate-specific antigen (PSA) response; secondary end-points included safety, tolerability and TTP.  Trabectedin resulted in PSA declines of greater than or equal to 50 % in 12.5 % (Cohort A) and 10.5 % (Cohort B2) of patients.  Among men pre-treated with taxanes-based chemotherapy, PSA response was 13.6 % (Cohort A) and 15.4 % (Cohort B2); PSA responses lasted 4.1 to 8.6 months, and median TTP was 1.5 months (Cohort A) and 1.9 months (Cohort B2).  The dose of 1.5 mg/m (2) (approved for STS) given as 24-hour IV infusion q3wk was not tolerable in these patients.  At 1.2 mg/m (2) q3wk and 0.58 mg/m (2) weekly, the most common adverse events were nausea, fatigue and transient neutropenia and transaminase increase.  The authors concluded that 2 different trabectedin schedules showed modest activity in metastatic CRPC.  They stated that further studies may require identification of predictive factors of response in prostate cancer.

Acikgoz et al (2015) stated that trabectedin is active against a variety of tumor cell lines.  The present study focused on the effect of trabectedin in cell proliferation, cell cycle progression, apoptosis and spheroid formation in prostate cancer stem cells (CSCs).  Cluster of differentiation (CD) 133+high/CD44+high prostate CSCs were isolated from the DU145 and PC-3 human prostate cancer cell line through flow cytometry.  These researchers studied the growth-inhibitory effects of trabectedin and its molecular mechanisms on human prostate CSCs and non-CSCs.  DU-145 and PC-3 CSCs were treated with 0.1, 1, 10 and 100 nM trabectedin for 24, 48 and 72 hours and the growth inhibition rates were examined using the sphere-forming assay.  Annexin-V assay and immunofluorescence analyses were performed for the detection of the cell death.  Concentration-dependent effects of trabectedin on the cell cycle were also evaluated.  The cells were exposed to the different doses of trabectedin for 24, 48 and 72 hours to evaluate the effect of trabectedin on the number and diameter of spheroids.  According to the results, trabectedin induced cytotoxicity and apoptosis at the IC50 dose, resulting in a significant increase expression of caspase-3, caspase-8, caspase-9, p53 and decrease expression of bcl-2 in dose-dependent manner.  Cell cycle analyses revealed that trabectedin induced dose-dependent G2/M-phase cell cycle arrest, particularly at high-dose treatments.  Three-dimensional culture studies showed that trabectedin reduced the number and diameter of spheroids of DU145 and PC3 CSCs.  Furthermore, these investigators found that trabectedin disrupted cell-cell interactions via E-cadherin in prostasphere of DU-145 and PC-3 CSCs.  The authors concluded that the results showed that trabectedin inhibited cellular proliferation and accelerated apoptotic events in prostate CSCs; and may be a potential effective therapeutic agent against prostate cancer.

Translocation-Related Sarcoma: Le Cesne et al (2012) stated that approximately 20 % of STSs have subtype-specific chromosomal translocations; these generate chimeric oncoproteins that can act as abnormal transcription factors.  Since trabectedin can bind to DNA and displace transcription factors, anti-tumor activity was explored in translocation-related sarcoma (TRS) subtypes.  This retrospective pooled analysis included data from 81 patients with TRS treated in 8 phase II clinical trials.  Translocation-related sarcoma subtypes were: synovial sarcoma (SS, n = 45), myxoid-round cell Liposarcoma (MRC-L-sarcoma, n = 27), alveolar soft part sarcoma (ASPS, n = 4), endometrial stromal sarcoma (ESS, n = 3) and clear cell sarcoma (CCS, n = 2).  All but 1 patient had received prior chemotherapy (median of 2 lines).  Patients received a median of 4 trabectedin cycles (range of 1 to 48; median dose intensity = 0.40 mg/m (2)/week).  Partial responses according to RECIST occurred in 8 patients (ORR = 10 %; 95 % CI: 4 to 19 %): 4 in MRC-L-sarcoma; 3 in SS and 1 in ESS.  Tumor control rate (ORR plus SD) was 59 % (95 % CI: 48 to 70 %).  Median PFS was 4.1 months (6-month PFS rate = 40 %).  Median OS was 17.4 months (survival rate at 12 months = 60 %).  Trabectedin had a manageable safety profile.  The authors concluded that trabectedin demonstrated encouraging disease control in TRS.  Since these promising results were generally noted in patients following chemotherapy, a phase III randomized trial in first-line is ongoing to compare trabectedin with doxorubicin-based chemotherapy (DXCT) in patients with TRS.

Zanardi et al (2014) reported the response achieved in a patient with lung metastases from SS.  A man with a large SS of the axilla underwent 3 cycles of neoadjuvant epirubicin+ifosfamide before complete excision, followed by 3 additional cycles of chemotherapy and radiotherapy.  After 14 months, bilateral lung metastases appeared and were first treated with a prolonged 14-day continuous infusion of high-dose ifosfamide without response, and then with second-line trabectedin.  A radiological PR was achieved; dosage was reduced to 1.1 mg/m(2) because of mild asthenia, grade 3 neutropenia, grade 3 nausea and vomiting, and reversible transaminase elevation.  After 9 months of treatment, the lung nodules progressed, the patient received sorafenib, but further progressed and died 19 months after the first appearance of lung metastases.  Trabectedin was the only drug that led to a radiological response in this patient with SS, despite being administered at 75 % of the standard dose because of dose-limiting nausea and vomiting, in line with more recent data demonstrating activity in translocated sarcomas.  The authors believed that trabectedin represents an attractive option for the treatment of metastatic SS and further clinical studies are needed.

In a randomized, phase III, clinical trial, Blay and colleagues (2014) evaluated first-line trabectedin versus DXCT in patients with advanced/metastatic TRS.  Patients were randomly assigned (1:1) to receive trabectedin 1.5 mg/m2 24-hour IV infusion every 3 weeks (q3wk) (Arm A), or doxorubicin 75 mg/m2 IV, q3wk, or doxorubicin 60 mg/m2 IV. plus ifosfamide (range of 6 to 9 g/m2) IV. q3wk (Arm B).  Progression-free survival by independent review was the primary efficacy end-point.  A total of 121 patients were randomized; 88 of them had TRS confirmed by central pathology review (efficacy population).  Twenty-nine PFS events were assessed by independent review (16 with trabectedin; 13 with DXCT); PFS showed non-significant difference between arms (stratified log rank test, p = 0.9573; HR = 0.86, p = 0.6992).  At the time of this analysis, 63.9 % and 58.3 % of patients were alive in trabectedin and DXCT arms, respectively.  There was no statistically significant difference in survival curves.  Response rate according to RECIST 1.0 was significantly higher in DXCT arm (27.0 % versus 5.9 %), but response according to Choi criteria showed fewer differences between treatment arms (45.9 % versus 37.3 %).  Safety profile was as expected for both arms, with higher incidence of severe neutropenia, alopecia and mucositis in the DXCT arm.  The authors concluded that neither trabectedin nor DXCT-based chemotherapy showed significant superiority in the first-line treatment of patients with advanced TRS.

In a randomized, open-label, phase II clinical trial, Kawai et al (2015) evaluated the safety and effectiveness of trabectedin as second-line therapy or later for patients with advanced TRS.  Eligible patients had pathological diagnosis of TRS, were aged 19 years or older, were unresponsive or intolerant to standard chemotherapy regimens, no more than 4 previous chemotherapy regimens, Eastern Cooperative Oncology Group (ECOG) performance status 0 or 1, adequate bone marrow reserve, renal and liver functions, and had measurable lesions.  Patients were randomly assigned (1:1) by the minimization method to receive either trabectedin (1.2 mg/m(2) given via a central venous line over 24 hours on day 1 of a 21 day treatment cycle) or best supportive care, which was adjusted centrally by pathological subtype.  Investigators, patients, and the sponsor were unmasked to the treatment assignment.  Progression-free survival and objective responses were assessed by a masked central radiology imaging review.  Effectiveness was assessed by masked central radiology imaging review.  The primary end-point was PFS for the full analysis set population.  Follow-up is ongoing for the patients under study treatment.  Between July 11, 2012, and January 20, 2014, a total of 76 patients were enrolled and allocated to receive either trabectedin (n = 39) or best supportive care (n = 37).  After central review to confirm pathological subtypes, 73 patients (37 in the trabectedin group and 36 in the best supportive care group) were included in the primary efficacy analysis.  Median PFS of the trabectedin group was 5.6 months (95 % CI: 4.1 to 7.5) and the best supportive care group was 0.9 months (0.7 to 1.0).  The HR for PFS of trabectedin versus best supportive care was 0.07 (90 % CI: 0.03 to 0.14 and 95 % CI: 0.03 to 0.16) by a Cox proportional hazards model (p < 0·0001).  The most common drug-related adverse events for patients treated with trabectedin were nausea (32 [89 %] of 36), decreased appetite (21 [58 %]), decreased neutrophil count (30 [83 %]), increased alanine aminotransferase (24 [67 %]), and decreased white blood cell count (20 [56 %]).  The authors concluded that trabectedin significantly reduced the risk of disease progression and death in patients with advanced TRS after standard chemotherapy such as doxorubicin, and should be considered as a new therapeutic treatment option for this patient population.  These findings need to be validated in well-designed phase III clinical trials.


Reference

1)    Aetna Medical Clinical Policy Bulletin. Trabectedin (Yondelis) accessed at http://www.aetna.com/cpb/medical/data/900_999/0903.html

2)    Yondelis Product Information. Janssen Products, LP. Horsham, PA. October 2015.

3)    Clinical Pharmacology.  Accessed online 3/14/2016.

Addendum:

1)    Effective 01/01/2017: added J9352 as appropriate code for Yondelis.


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