Translocation-related Sarcomas Research Articles

Subtype-selective induction of apoptosis in translocation-related sarcoma cells induced by PUMA and BIM upon treatment with pan-PI3K inhibitors

Translocation-related sarcomas (TRSs) harbor an oncogenic fusion gene generated by chromosome translocation and account for approximately one-third of all sarcomas; however, effective targeted therapies have yet to be established. We previously reported that a pan-phosphatidylinositol 3-kinase (PI3K) inhibitor, ZSTK474, was effective for the treatment of sarcomas in a phase I clinical trial. We also demonstrated the efficacy of ZSTK474 in a preclinical model, particularly in cell lines from synovial sarcoma (SS), Ewing’s sarcoma (ES) and alveolar rhabdomyosarcoma (ARMS), all of which harbor chromosomal translocations. ZSTK474 selectively induced apoptosis in all these sarcoma cell lines, although the precise mechanism underlying the induction of apoptosis remained unclear. In the present study, we aimed to determine the antitumor effect of PI3K inhibitors, particularly with regards to the induction of apoptosis, against various TRS subtypes using cell lines and patient-derived cells (PDCs). All of the cell lines derived from SS (six), ES (two) and ARMS (one) underwent apoptosis accompanied by the cleavage of poly-(ADP-ribose) polymerase (PARP) and the loss of mitochondrial membrane potential. We also observed apoptotic progression in PDCs from SS, ES and clear cell sarcoma (CCS). Transcriptional analyses revealed that PI3K inhibitors triggered the induction of PUMA and BIM and the knockdown of these genes by RNA interference efficiently suppressed apoptosis, suggesting their functional involvement in the progression of apoptosis. In contrast, TRS-derived cell lines/PDCs from alveolar soft part sarcoma (ASPS), CIC-DUX4 sarcoma and dermatofibrosarcoma protuberans failed to undergo apoptosis nor induce PUMA and BIM expression, as well as cell lines derived from non-TRSs and carcinomas. Thus, we conclude that PI3K inhibitors induce apoptosis in selective TRSs such as ES and SS via the induction of PUMA and BIM and the subsequent loss of mitochondrial membrane potential. This represents proof of concept for PI3K-targeted therapy, particularly such TRS patients.

Transcription regulators and ultra-rare and other rare translocation-related sarcomas treated with trabectedin: A proof of principle from a post-hoc analysis.

Among sarcomas, which are rare cancers with an incidence of <6 per 100.000/year cases, ultra-rare sarcomas have an incidence of approximately ≤1/1,000,000/year cases and altogether account for ~20% of all soft tissue sarcomas (STS) and bone sarcomas. The Italian Sarcoma Group has recently performed a non-interventional, retrospective TrObs study with data from 512 anthracycline-pretreated patients with advanced multiple STS histologies and treated with trabectedin (Palmerini, Cancers 2021; ClinicalTrials.gov Identifier: NCT02793050). A post-hoc analysis of case series to evaluate the efficacy and safety of trabectedin on patients with ultra-rare and other rare translocation-related sarcomas included in TrObs study was performed. Main outcomes comprised investigator-assessed overall response rate (ORR), disease control rate (DCR), progression-free survival (PFS) and safety. Thirty-six patients (18 women) with ultra-rare and other rare sarcoma and a median age of 53.0 years (range: 22-81) were included. Most patients had solitary fibrous tumor (SFT; n=11) followed by epithelioid sarcoma (n=5), malignant peripheral nerve sheath tumor (MPNST; n=4), extraskeletal myxoid chondrosarcoma (EMC; n=3), desmoplastic small round cell tumor (DSRCT; n=3), and alveolar soft part sarcoma (ASPS), rhabdomyosarcoma and clear cell sarcoma (n=2 each). Thirty-five patients had metastatic disease and 23 patients received trabectedin as a second-line treatment. Among 35 patients evaluable for response, two patients with SFT and ASPS had a partial response and one patient with DSRCT obtained a complete response, reaching an ORR of 8.6% (95% CI: 2.8-23.4%). Among patients with an ORR, 6-months PFS was 100% in patients with ASPS, 45.7% in patients with SFT and 33.3% in those with DSRCT. Two patients with epithelioid sarcoma and myoepithelioma had disease stabilization lasting >24 months. Nine patients had at least one grade 3/4 adverse event, mostly being bone marrow toxicity (n=6). Trabectedin has some anti-tumor activity in some ultra-rare and other rare sarcomas, particularly translocation-related sarcomas, with the well-known manageable safety profile.

Abstract 1844: Anti-tumor activity of a dual BET/CBP/EP300 inhibitor, NEO2734, in undifferentiated pleomorphic sarcomas and identification of genes involved in resistance

Abstract Introduction: Undifferentiated pleomorphic sarcoma is the most frequent and the most aggressive sarcoma subtype. Despite adequate locoregional treatment, up to 40% will develop metastatic disease. Doxorubicin represents the standard 1st line of treatment for patient with advanced disease. However, its activity is limited with a response rate of only 10% and a progression-free survival of less than 6-months. Identification of new therapeutic strategies is therefore an important medical need. Bromodomain and extra-terminal domain (BET) proteins, cyclic adenosine monophosphate response element-binding protein (CBP), and the E1A-binding protein of p300 (EP300) are important players in histone acetylation. BET inhibitors have already shown pre-clinical activity in translocation-related sarcomas such as Ewing tumors. However, BET and dual BET/P300 inhibitors could have also relevant anti-tumor activity if MYC driven tumors. We previously found that at least a subgroup of UPS is characterized by a strong expression of MYC-targets pathway (Toulmonde et al, EBIOMEDICINE, 2020) Methods: The anti-tumor activity of three compounds which inhibits either CBP/P300 only (CPI-637) or dual inhibitors of both BET and CBP/P300 proteins (NEO1132 and NEO2437) was investigated in four UPS cell lines and two patient-derived xenografts (PDX) established at Institut Bergonié (Bordeaux, France). A CRISPR-KO screen was used to identify genes that mediate resistance to NEO2734. Results: We found that the 3 compounds act mainly by inhibiting the cell cycle with a concomitant reduction of MYC expression. NEO2734 was the most potent one with IC50 range between 0.2 to 1 µM in vitro and an antitumor activity in vivo in the two PDX models of UPS. To investigate the mechanism of action, we performed a transcriptomic analysis by RNA-sequencing. Gene set enrichment analysis revealed that NEO2734 induced a downregulation of G2M checkpoint and E2F targets hallmarks. We confirmed these results at the protein level showing a downregulation of several proteins involved in these pathways such as PLK1, AURKA or CCNB1. Interestingly, two of our four UPS cells lines were resistant to NEO2734 (IC50 27µM and 73µM). To elucidate the genetic factors involved in this resistance, we performed a CRISPR-KO screen. We identified more than 200 genes as potential candidates involved in drug resistance and decided to focus on hnRNPU which is an interactor of P300 and play a role in cell cycle regulation through the formation of the mitotic spindle with PLK1 and AURKA. Conclusion: Dual inhibition of BET and CBP/P300 proteins has promising antitumor activity in undifferentiated pleomorphic sarcoma. Suppressing hnRNPU may enhance the activity of dual BET and P300/CBP bromodomain inhibitor in sarcoma and other cancers. Citation Format: Stephanie Verbeke, Frederic Bertolo, Vanessa Chaire, Aurelien Bourdon, Amina Naït Eldjoudi, Marie-Alix Derieppe, Francis Giles, Antoine Italiano. Anti-tumor activity of a dual BET/CBP/EP300 inhibitor, NEO2734, in undifferentiated pleomorphic sarcomas and identification of genes involved in resistance [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 1844.

Detection of sarcoma fusions by a next-generation sequencing based–ligation-dependent multiplex RT-PCR assay

Morphological, immunohistochemical, and molecular methods often need to be combined for accurate diagnosis and optimal clinical management of sarcomas. Here, we have developed, a new molecular diagnostic assay, for the detection of gene fusions in sarcomas. This targeted multiplexed next-generation sequencing (NGS)-based method utilizes ligation dependent reverse-transcriptase polymerase chain reaction (LD-RT-PCR-NGS) to detect oncogenic fusion transcripts involving 137 genes, leading to 139 gene fusions known to be recurrently rearranged in soft-tissue and bone tumors. 158 bone and soft-tissue tumors with previously identified fusion genes by fluorescent in situ hybridization (FISH) or RT-PCR were selected to test the specificity and the sensitivity of this assay. RNA were extracted from formalin-fixed paraffin-embedded (n = 143) or frozen (n = 15) material (specimen; n = 42 or core needle biopsies; n = 116). Tested tumors encompassed 23 major translocation-related sarcomas types, including Ewing and Ewing-like sarcomas, rhabdomyosarcomas, desmoplastic small round-cell tumors, clear-cell sarcomas, infantile fibrosarcomas, endometrial stromal sarcomas, epithelioid hemangioendotheliomas, alveolar soft-part sarcomas, biphenotypic sinonasal sarcomas, extraskeletal myxoid chondrosarcomas, myxoid/round-cell liposarcomas, dermatofibrosarcomas protuberans and solitary fibrous tumors. In-frame fusion transcripts were detected in 98.1% of cases (155/158). Gene fusion assay results correlated with conventional techniques (FISH and RT-PCR) in 155/158 tumors (98.1%). These data demonstrate that this assay is a rapid, robust, highly sensitive, and multiplexed targeted RNA sequencing assay for the detection of recurrent gene fusions on RNA extracted from routine clinical specimens of sarcomas (formalin-fixed paraffin-embedded or frozen). It facilitates the precise diagnosis and identification of tumors with potential targetable fusions. In addition, this assay can be easily customized to cover new fusions.

Improving Immunotherapy Efficacy in Soft-Tissue Sarcomas: A Biomarker Driven and Histotype Tailored Review.

Anti-PD-(L)1 therapies yield a disappointing response rate of 15% across soft-tissue sarcomas, even if some subtypes benefit more than others. The proportions of TAMs and TILs in their tumor microenvironment are variable, and this heterogeneity correlates to histotype. Tumors with a richer CD8+ T cell, M1 macrophage, and CD20+ cells infiltrate have a better prognosis than those infiltrated by M0/M2 macrophages and a high immune checkpoint protein expression. PD-L1 and CD8+ infiltrate seem correlated to response to immune checkpoint inhibitors (ICI), but tertiary lymphoid structures have the best predictive value and have been validated prospectively. Trials for combination therapies are ongoing and focus on the association of ICI with chemotherapy, achieving encouraging results especially with pembrolizumab and doxorubicin at an early stage, or ICI with antiangiogenics. A synergy with oncolytic viruses is seen and intratumoral talimogene laherpavec yields an impressive 35% ORR when associated to pembrolizumab. Adoptive cellular therapies are also of great interest in tumors with a high expression of cancer-testis antigens (CTA), such as synovial sarcomas or myxoid round cell liposarcomas with an ORR ranging from 20 to 50%. It seems crucial to adapt the design of clinical trials to histology. Leiomyosarcomas are characterized by complex genomics but are poorly infiltrated by immune cells and do not benefit from ICI. They should be tested with PIK3CA/AKT inhibition, IDO blockade, or treatments aiming at increasing antigenicity (radiotherapy, PARP inhibitors). DDLPS are more infiltrated and have higher PD-L1 expression, but responses to ICI remain variable across clinical studies. Combinations with MDM2 antagonists or CDK4/6 inhibitors may improve responses for DDLPS. UPS harbor the highest copy number alterations (CNA) and mutation rates, with a rich immune infiltrate containing TLS. They have a promising 15-40% ORR to ICI. Trials for ICB should focus on immune-high UPS. Association of ICI with FGFR inhibitors warrants further exploration in the immune-low group of UPS. Finally translocation-related sarcomas are heterogeneous, and although synovial sarcomas a poorly infiltrated and have a poor response rate to ICI, ASPS largely benefit from ICB monotherapy or its association with antiangiogenics agents. Targeting specific neoantigens through vaccine or adoptive cellular therapies is probably the most promising approach in synovial sarcomas.

Trabectedin in Advanced Sarcomas-Experience at a Tertiary Care Center and Review of Literature.

Background There is sparse literature on trabectedin in advanced soft-tissue sarcomas from developing world. It would be interesting to know about use and outcomes of trabectedin in Indian patients. Method In a retrospective study, consecutive patients treated with trabectedin from 2016 to 2019 were analyzed. Patients with L-sarcomas were treated at a dose of 1.5 mg/m 2 , while those with translocation-related sarcomas were treated at a dose of 1.2 mg/m 2 as a 24-hour infusion through peripherally inserted central catheter line. From July 2019, infusions were administered through an ambulatory elastomeric pump, while before that patients were admitted for 24 hours. We used SPSS version 23.0 for statistical calculation. Result A total of 20 patients received trabectedin with a total of 116 infusions. The median age was 46 years (range: 22–73 years). The male ( n = 11, 55%) and female patients were almost equal ( n = 9, 45%). Thirteen patients (65%) had Eastern Cooperative Oncology Group Performance Status 1. Majority of the patients had leiomyosarcoma ( n = 8, 40%); remaining comprised of liposarcoma (3, 15%), translocation-related sarcomas excluding myxoid liposarcoma ( n = 8, 40%) and others ( n = 1,5%). Most common site was extremity ( n = 11, 55%) followed by retroperitoneal ( n = 3, 15%), visceral ( n = 3, 15%), and others ( n = 3,15%). Median number of previous lines received was 2 (range: 0–4). Median number of trabectedin cycles received was 4 (range: 1–17). Best response assessed was stable disease ( n = 10, 50%), progressive disease ( n = 6, 30%), partial response ( n = 1, 5%), and not assessed in 3 patients. After a median follow-up of 19 months, median progression-free survival was 4 months. Conclusion In this heavily treated population (composed of L-sarcomas and translocation-related sarcomas) with many patients with poor performance status, the outcome with trabectedin is in synchrony with literature. However, the need of 24-hour admission might deter quality of life. Elastomeric pump seems to be a reasonable alternative to admission and can be a breakthrough in administering trabectedin, especially in developing countries.

Translocation-Related Sarcomas.

Chromosomal translocations are observed in approximately 20% of soft tissue sarcomas (STS). With the advances in pathological examination technology, the identification of translocations has enabled precise diagnoses and classifications of STS, and it has been suggested that the presence of and differences in translocations could be prognostic factors in some translocation-related sarcomas. Most of the translocations in STS were not regarded as targets of molecular therapies until recently. However, trabectedin, an alkylating agent, has shown clinical benefits against translocation-related sarcoma based on a modulation of the transcription of the tumor’s oncogenic fusion proteins. Many molecular-targeted drugs that are specific to translocations (e.g., anaplastic lymphoma kinase and tropomyosin kinase related fusion proteins) have emerged. The progress in gene technologies has allowed researchers to identify and even induce new translocations and fusion proteins, which might become targets of molecular-targeted therapies. In this review, we discuss the clinical significance of translocation-related sarcomas, including their diagnoses and targeted therapies.

Presentation and outcome of frequent and rare sarcoma histologic subtypes: A study of 10,262 patients with localized visceral/soft tissue sarcoma managed in reference centers.

The objective of this study was to describe characteristics at diagnosis and outcomes of adults with soft tissue sarcoma. The authors conducted a retrospective multicenter study of 12,262 patients who were treated between January 1980 and 31 December 2013 in French Sarcoma Group centers and enrolled in the "Conticabase." Diagnoses were systematically reviewed by expert pathologists, and entities were classified according to the 2013 World Health Organization classification. Diagnostic characteristics, treatments, and outcomes are described for the entire cohort, for the subgroup of patients with translocation-related sarcomas, and for 9 different histologic subtypes. The results stressed the magnitude of heterogeneity among adult sarcomas. For example, compared with other sarcomas, translocation-related sarcomas (2143 tumors; 20.8%) were associated with a younger age at presentation (40.6 vs 60.0 years; P < .0001), a low rate of predisposing conditions (0.01% vs 22.3%; P < .0001), a higher rate of lymph node involvement (4.7% vs 1.3%; P < .0001), and a higher rate of synchronous metastasis (11.9% vs 6.7%; P < .001); and complete (R0) resection (41.6% vs 31.9%; P < .0001), receipt of (neo)adjuvant radiation therapy (62.6% vs 42.2%; P < .0001), and receipt of (neo)adjuvant chemotherapy (36.6% vs 22.3%; P < .0001) were significantly more frequent. Overall, translocation-related sarcomas were associated with a lower rate of local relapse (18.1% vs 26.0%; P < .0001) but a higher rate of metastatic relapse (42.0% vs 30.7%; P < .0001). Collaborative efforts are urgently needed to better assess the natural history and management options for every histologic subtype of sarcoma. Cancer 2018;124:1179-87. © 2017 American Cancer Society.

Diagnostic utility of automated SureFISH (Dako Omnis) in the diagnosis of musculoskeletal translocation-related sarcomas.

Fluorescence in situ hybridization (FISH) is an essential tool for genetic diagnosis in daily pathological work. Almost full automation of FISH can be achieved with the recently released automated SureFISH platform (Dako Omnis, Agilent Technologies, Santa Clara, CA, USA). Its utility has been reported in HER2 amplification of breast and gastric carcinoma and ALK-rearranged lung cancer. Here, we examined the utility of automated SureFISH for the identification of rearrangement signals in translocation-related sarcomas (TRSs), including 11 EWSR1-rearranged and 10 synovial sarcoma cases, compared with non-automated conventional FISH using the same specimens. The percentages of EWSR1 or SS18 split signals were higher in automated SureFISH than in conventional FISH in 13 of the 21 cases. On the other hand, 8 of the 21 cases showed the same or lower percentage of split signals in automated SureFISH. Both FISH approaches detected EWSR1 and SS18 split signals in more than 10% of tumor cells in all cases. The strongest advantage of automated SureFISH is its ability to reduce running time without sacrificing quality. Other advantages include improved signal sharpness with oligo probes and reduced ecological toxicity by avoiding formamide use. Automated SureFISH is an excellent tool for the genetic diagnosis of TRSs and contributes to their rapid definitive diagnosis.

Genetic landscape of soft-tissue sarcomas: Moving toward personalized medicine.

11002 Background: Patients with advanced soft-tissue sarcomas have a very poor outcome with a median overall survival of less than 18 months. Identification of molecular abnormalities for which targeted therapies are available or can be developed is critical for improving their outcomes. Methods: We have analyzed the mutational and copy number profiles of patients with sarcoma sequenced through the AACR Project GENIE Consortium in order to identify the proportion of cases bearing actionable mutation. Results: 587 patients (pts) were included in the study (295 males). 331 pts (56%) had complex genomics sarcomas, 144 (25%) translocation-related sarcomas and 112 (19%) others sarcomas (inactivating mutation, simple amplicon). The five most frequent histology were: Leiomyosarcoma (n = 112; 19.1%); Undifferentiated Pleomorphic Sarcomas (n = 74, 12.6%), dedifferentiated liposarcoma (n = 55, 9.4 %), angiosarcoma (n = 43, 7.3%), synovial sarcoma (n = 38, 6.5%). 430 pts (73%) had at least one mutation. The ten most frequently mutated genes were: TP53 (34.7%); ATRX (9.1%), RB1 (8.4%), KMT2D (5.8%), NF1 (5.3%), ATM (5.1%), PI3KCA (4.9%), ERBB4 (4.2%), PTEN (4%), and ARID1A (3.7%). 504 patients (85.9%) presented at least one copy number alteration. The 5 five most frequently amplified genes were: MDM2 (20%), CDK4 (16.7%), GLI1, MAP2KA, and TERT (3.2% for each gene), and the most frequently deleted were RB1 (12.7%), CDKN2A (10.3%), CDKN2B (9.7%), TP53(9.5%), PTEN (8.5). 92.5% of pts had at least one targetable mutation, copy number alteration and/or fusion gene ( Leiomyosarcoma n = 100/17%, UPS n = 74/12%, dedifferentiated diposarcoma n = 54/9%, angiosarcoma n = 41/7%, synovial Sarcoma n = 36/6%), with incidences reported that will be reported in details at the meeting. Conclusions: This is the first large report of genomic landscape including mutation and copy number profiling through NGS of soft-tissue sarcomas. Our results indicate a significant proportion of actionable mutations and represent a rationale for the MULTISARC study: the first study implementing Exome Seq and RNA Seq for clinical decision making in patients with advanced STS. The design of this study supported by the French government and launched in 09/2017 will be presented at the meeting.

Practical use and utility of fluorescence in situ hybridization in the pathological diagnosis of soft tissue and bone tumors.

During routine pathological examination, fluorescence in situ hybridization (FISH) plays a significant role in the genetic analysis of samples. FISH can detect genetic abnormalities such as chromosomal translocations, gene amplifications, and deletions in formalin-fixed, paraffin-embedded (FFPE) specimens. Due to its practical advantages, FISH is already used in many pathology laboratories. It is especially useful for the diagnosis of translocation-related sarcomas (TRSs), which comprise about 25% of soft tissue sarcomas. Because TRSs have specific chimeric genes derived from characteristic chromosomal translocations, their diagnosis would not be possible without FISH. FISH significantly contributes to the genetic confirmation of TRS. Analysis using next-generation sequencing (NGS), the latest powerful method for comprehensive genomic analysis, has recently revealed many kinds of chromosomal translocations in various TRSs. We often use experimental results to create custom probes for FISH and have applied NOCA2 split probes and CIC split, CIC-FOXO4 fusion probes to the pathological diagnosis of soft tissue angiofibroma and CIC-rearranged sarcoma, respectively. Some chimeric fusions detected by NGS induce the expression of related proteins and their detection using immunohistochemistry is beneficial for pathological diagnosis. We previously identified characteristic FOSB expression in pseudomyogenic hemangioendothelioma (PHE) with a specific SERPINE1-FOSB fusion, revealing the usefulness of FOSB immunohistochemistry in the differential diagnosis of PHE and its mimics. Finally, we participated in a central review of a clinical trial of trabectedin monotherapy. We guaranteed an accurate diagnosis by using FISH and genetic confirmation to select appropriate TRS patients and thereby confirm the accuracy of the patient enrollment of the clinical trial. FISH is an essential tool for the pathological diagnosis of soft tissue and bone tumors. It can detect various genetic abnormalities in an "in situ" fashion using FFPE specimens on glass slides during routine examination. It is also an excellent tool for translating the latest experimental findings to practical use in routine pathological diagnosis. Further instrumental improvements in FISH will help it to become the universal method for the genetic analysis of pathological diagnoses.

ISY-13-4 - Clinical trials of trabectedin for soft tissue sarcoma

Doxorubicin and ifosfamide are the two main effective therapies for STS, but few therapeutic options exist after those two therapies.Trabectedin, a marine-derived anti-tumor agent, exerts its anti-tumor activity by inhibiting DNA repair through its binding to the DNA minor groove, and it also inhibits transcription factors derived from fusion proteins. It is effective for soft tissue sarcomas (STS), especially translocation-related sarcomas (TRS).Pooled analysis from five phase II studies of trabectedin (n = 350, pre-treated in 91%) showed 10% response rate, 28.3% disease-control rate, and OS of 13-14 months.In a randomized phase III study comparing trabectedin or dacarbazine (2:1) for pts with advanced liposarcoma or leiomyosarcoma pretreated with anthracycline and other cytotoxic drug (n = 518), trabectedin showed improvement in PFS (HR 0.55, 4.2M vs 1.5M), but did not show improvement in OS (HR 0.87). Most common Grade 3-4 adverse events were myelosuppression and transient elevation of transaminases.In Japan, randomized open label phase II study comparing trabectedin 1.2mg/m2 versus best supportive care in pts with TRS unresponsive or intolerant to standard chemotherapy, trabectedin showed improvement of PFS (HR 0.07, 5.6M versus 0.9M). Common adverse events were nausea, decreased appetite, decreased neutrophil, increased ALT, common and adverse events of G3 or more were neutrophil decreased (67%), ALT increased (61%), febrile neutropenia (14%). G4 rhabdomyolysis were also seen (3%).From these data, trabectedin was approved for STS in Japan at 2015 and should be considered as a therapeutic option for pretreated STS, especially TRS. Doxorubicin and ifosfamide are the two main effective therapies for STS, but few therapeutic options exist after those two therapies. Trabectedin, a marine-derived anti-tumor agent, exerts its anti-tumor activity by inhibiting DNA repair through its binding to the DNA minor groove, and it also inhibits transcription factors derived from fusion proteins. It is effective for soft tissue sarcomas (STS), especially translocation-related sarcomas (TRS). Pooled analysis from five phase II studies of trabectedin (n = 350, pre-treated in 91%) showed 10% response rate, 28.3% disease-control rate, and OS of 13-14 months. In a randomized phase III study comparing trabectedin or dacarbazine (2:1) for pts with advanced liposarcoma or leiomyosarcoma pretreated with anthracycline and other cytotoxic drug (n = 518), trabectedin showed improvement in PFS (HR 0.55, 4.2M vs 1.5M), but did not show improvement in OS (HR 0.87). Most common Grade 3-4 adverse events were myelosuppression and transient elevation of transaminases. In Japan, randomized open label phase II study comparing trabectedin 1.2mg/m2 versus best supportive care in pts with TRS unresponsive or intolerant to standard chemotherapy, trabectedin showed improvement of PFS (HR 0.07, 5.6M versus 0.9M). Common adverse events were nausea, decreased appetite, decreased neutrophil, increased ALT, common and adverse events of G3 or more were neutrophil decreased (67%), ALT increased (61%), febrile neutropenia (14%). G4 rhabdomyolysis were also seen (3%). From these data, trabectedin was approved for STS in Japan at 2015 and should be considered as a therapeutic option for pretreated STS, especially TRS.

Retrospective inter- and intra-patient evaluation of trabectedin after best supportive care for patients with advanced translocation-related sarcoma after failure of standard chemotherapy

AimOur randomised phase II study showed the clinical benefit of trabectedin compared with best supportive care (BSC) in patients with advanced translocation-related sarcomas after the failure of standard chemotherapy. The aim of the present study was to evaluate efficacy and safety of trabectedin in the identical patients crossed over to trabectedin after disease progression in the BSC arm of the randomised study. Patients and methodsThis was a single-arm study of the BSC patients of the randomised study in whom disease progressed. Trabectedin (1.2 mg/m2) was administered over 24 h on day 1 of a 21-d treatment cycle. The efficacy and safety of trabectedin after BSC were evaluated and retrospectively compared with the results of the randomised study. ResultsThirty patients crossed over to trabectedin. Median progression-free survival (PFS) was 7.3 months (95% confidence interval [CI]: 2.9–9.1) after crossover compared with 0.9 months (95% CI: 0.9–1.0) at BSC in the randomised study. PFS in the present study was comparable to that of the trabectedin arm in the randomised study. The number of patients with growth modulation index ≥1.33 was 25 (86%). Individual tumour volume was decreased in 11 patients after crossover. Adverse drug reactions (ADRs) were observed in 27 patients (96.4%). ADRs of grade III–IV were mainly bone marrow suppression and abnormal liver functions. ConclusionTrabectedin was revealed to be effective and well tolerated in the identical patients crossed over to trabectedin after disease progression in BSC.The present study is registered with the Japan Pharmaceutical Information Center, number JapicCTI-121853.

3445A Final results of a randomized phase II study comparing trabectedin and best supportive care (BSC) in patients (pts) with translocation-related sarcomas (TRS)

3445A Final results of a randomized phase II study comparing trabectedin and best supportive care (BSC) in patients (pts) with translocation-related sarcomas (TRS)

Trabectedin monotherapy after standard chemotherapy versus best supportive care in patients with advanced, translocation-related sarcoma: a randomised, open-label, phase 2 study

Trabectedin binds to the minor groove of DNA and blocks DNA repair machinery. Preclinical data have shown that trabectedin also modulates the transcription of the oncogenic fusion proteins of translocation-related sarcomas. We aimed to assess the efficacy and safety of trabectedin as second-line therapy or later for patients with advanced translocation-related sarcoma. We did a multicentre randomised open-label study in Japan. Eligible patients had pathological diagnosis of translocation-related sarcoma, were aged 19 years or older, were unresponsive or intolerant to standard chemotherapy regimens, no more than four previous chemotherapy regimens, Eastern Cooperative Oncology Group 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 minimisation method to receive either trabectedin (1·2 mg/m(2) given via a central venous line over 24 h 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. Efficacy was assessed by masked central radiology imaging review. The primary endpoint was progression-free survival for the full analysis set population. Follow-up is ongoing for the patients under study treatment. The study is registered with Japan Pharmaceutical Information Center, number JapicCTI-121850. Between July 11, 2012, and Jan 20, 2014, 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 progression-free survival of the trabectedin group was 5·6 months (95% CI 4·1-7·5) and the best supportive care group was 0·9 months (0·7-1·0). The hazard ratio (HR) for progression-free survival of trabectedin versus best supportive care was 0·07 (90% CI 0·03-0·14 and 95% CI 0·03-0·16) 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%]). Trabectedin significantly reduced the risk of disease progression and death in patients with advanced translocation-related sarcoma after standard chemotherapy such as doxorubicin, and should be considered as a new therapeutic treatment option for this patient population. Taiho Pharmaceutical Co., Ltd.

35 BRCA1 expression exploratory analysis in patients of the phase III trial of trabectedin vs. doxorubicin-based chemotherapy as first-line therapy in translocation-related sarcomas

35 BRCA1 expression exploratory analysis in patients of the phase III trial of trabectedin vs. doxorubicin-based chemotherapy as first-line therapy in translocation-related sarcomas

Intra- and Inter-Patient Comparison of Efficacy Between Two Phase Ii Studies of Trabectedin (T) in Patients (Pts) with Translocation-Related Sarcomas (Trs); a Randomized Comparative Study (Study-C) and a Single Arm Study (Study-S)

ABSTRACT Aim: T binds to the minor groove of DNA and blocks DNA repair machinery. In addition, T inhibits interactions of transcription factors with DNA. It has been reported that T is an active drug in TRS pts unresponsive to available chemotherapies with a significant increase in progression-free survival (PFS) and overall survival in study-C (ASCO 2014, Abstract: 10524). For pts with confirmed disease progression in best supportive care (BSC) arm of study-C, study-S as a rescue therapy was conducted to evaluate safety and efficacy of T. Efficacy for pts who were enrolled in both studies and efficacy difference for T between study-C and study-S were evaluated. Methods: Target population of study-C was pts with histologically proven TRS of 14 types and unresponsive or intolerable to standard chemotherapy. After confirmation of disease progression based on image assessments in study-C, pts who were assigned to BSC were enrolled in study-S if they signed a consent form. Pts received T as a 24-hour continuous infusion every 21 days. We analyzed intra-patient comparison between BSC in study-C (BSC/C) and T in study-S (T/S), and inter-patient comparison between T in study-C (T/C) and T/S. We used a multivariate Cox proportional hazard model adjusted by background factors to estimate hazard ratios (HRs) for PFS in these comparisons. Results: In study-C, 76 pts were randomized: 39 in T and 37 in BSC arm. Out of 37 pts in BSC arm of study-C, 31 pts were enrolled in study-S. Number of pts for efficacy analysis of T/C, BSC/C and T/S were 37, 29 and 29 respectively. Median PFS (95% confidence interval) for T/C, BSC/C and T/S were 5.6 month (m) (4.1-7.5), 0.9 m (0.9-1.0), and 7.3 m (2.9 -9.1), respectively. HRs for PFS in intra- (BSC/C vs T/S) and inter-patient (T/C vs T/S) comparison were 0.08 (P Conclusions: PFS was significantly prolonged in T/S compared with BSC/C, and was not different between T/C and T/S. Although contribution to survival is not evaluated, it is expected T could suppress progress of advanced TRS even at the late stage. Disclosure: T. Ueda: I disclose that I have a consultant or advisory relationship with Daiichi-Sankyo Pharmaceutical Co.Ltd.; A. Kawai: I disclose that I have received Honoraria from TAIHO, GSK, MSD and Eisai. All other authors have declared no conflicts of interest.

A randomized phase II study comparing trabectedin (T) and best supportive care (BSC) in patients (pts) with translocation-related sarcomas (TRS).

10524 Background: T binds to the minor groove of DNA and blocks DNA repair machinery following the inhibition of cell cycle and proliferation. In addition, T inhibits interactions of transcription ...

Phase I and pharmacokinetic study of trabectedin, a DNA minor groove binder, administered as a 24-h continuous infusion in Japanese patients with soft tissue sarcoma

Summary Background Trabectedin is a novel anticancer agent used to treat soft tissue sarcoma (STS). This phase I study of trabectedin was performed to determine the recommended dose for phase II studies in Japanese patients with STS. Methods Patients who had STS refractory to, or who could not tolerate, anthracycline-based chemotherapy were enrolled. The starting dose of trabectedin was 0.9 mg/m2, given as a 24-h continuous infusion every 21 days. The dose was escalated to 1.2 mg/m2 and then to 1.5 mg/m2, using a “3 + 3” cohort expansion design. Plasma samples were collected for pharmacokinetic analysis. Results Fifteen patients received 1 of 3 dose levels of trabectedin. Dose-limiting toxicity occurred in two of three patients at 1.5 mg/m2: 1 had a grade 3 increase in creatine phosphokinase and grade 3 anorexia, and the other had grade 4 platelet count decreased. Frequent grade 3 or 4 adverse events (AEs) included elevations of alanine aminotransferase and aspartate aminotransferase and decrease in neutrophil count. The frequency and severity of AEs were clearly greater at 1.5 mg/m2 than at the lower doses. Pharmacokinetic analysis showed that the area under the concentration-time curve at a dose of 1.2 mg/m2 was adequate to produce antitumor activity. A partial response was obtained in three patients with translocation-related sarcomas (1 each with myxoid liposarcoma, synovial sarcoma, and extraskeletal Ewing sarcoma). Conclusions The recommended dose of trabectedin for phase II studies is 1.2 mg/m2 in Japanese patients with STS. Trabectedin may be especially effective against translocation-related sarcomas.

Randomised phase III trial of trabectedin versus doxorubicin-based chemotherapy as first-line therapy in translocation-related sarcomas

AimThis randomised phase III trial evaluated first-line trabectedin versus doxorubicin-based chemotherapy (DXCT) in patients with advanced/metastatic translocation-related sarcomas (TRS). MethodsPatients were randomly assigned (1:1) to receive trabectedin 1.5mg/m2 24-h intravenous (i.v.) infusion every 3weeks (q3wk) (Arm A), or doxorubicin 75mg/m2 i.v. q3wk, or doxorubicin 60mg/m2 i.v. plus ifosfamide (range, 6–9g/m2) i.v. q3wk (Arm B). Progression-free survival (PFS) by independent review was the primary efficacy end-point. ResultsOne hundred and twenty-one patients were randomised; 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; hazard ratio=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 Response Evaluation Criteria in Solid Tumours (RECIST) v.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. ConclusionNeither trabectedin nor doxorubicin-based chemotherapy showed significant superiority in the first-line treatment of patients with advanced translocation-related sarcoma.