Treatment Of Advanced Soft Tissue Sarcoma Research Articles

Efficacy of eribulin administered in combination with an immune checkpoint inhibitor (ICI) and anlotinib as salvage treatment for patients (pts) with advanced adult soft tissue sarcoma (STS).

11572 Background: Eribulin combined with a multi-targeted antiangiogenic tyrosine kinase inhibitor has shown efficacy in STS. ICIs have also exhibited improved survival in some STS subtypes. We investigated the efficacy and safety of triple combination therapy with eribulin, an ICI and anlotinib in the treatment of advanced STS in an adult Chinese population. Methods: This study retrospectively analyzed data from patients diagnosed with advanced STS who received combination therapy with eribulin, an ICI and anlotinib at the Department of Oncology, Zhongshan Hospital affiliated to Fudan University. The primary endpoint was progression-free survival (PFS). Secondary endpoints included objective response rate (ORR) by RECIST v1.1, disease control rate (DCR), and treatment-related adverse events (TRAEs) by CTCAE v5.0. Results: Medical records from 32 pts treated between August 15, 2020 and January 31, 2023 were included; the median age was 56 years, 71.8% (23/32) were female, 75.0% (24/32) had an Eastern Cooperative Oncology Group (ECOG) performance status (PS) of 0 or 1, and 25.0% (8/32) had an ECOG PS of 2. Pts had received a median of 2 (range 0-6) prior regimens and the median follow-up was 4.1 months. Among the patients, 50.0% (16/32) had liposarcomas (including 1 with pleomorphic liposarcoma and 15 with dedifferentiated liposarcoma [DDLPS]), 31.3% (10/32) had leiomyosarcomas (LMS), 3 had undifferentiated pleomorphic sarcoma (UPS), and 1 each had angiosarcoma, rhabdomyosarcoma and desmoplastic small round cell tumor. In a preliminary analysis, 29 pts were evaluable for clinical activity; partial responses (PRs) were achieved in 3 pts (2 DDLPS, 1 UPS), the ORR and DCR were 10.3% (3/29) and 62.1% (18/29) respectively, and the median PFS was 5.7 months (95% CI 2.7-9.8). Of the 15 pts with DDLPS (median 1 prior line of therapy; median follow-up 6.3 months), 13 were evaluable for clinical activity; a PR was achieved by 15.4% (2/13), the DCR was 61.5% (8/13), the median PFS was 9.8 months (95% CI 1.8-28.5) and treatment was ongoing in 46.7% of pts (n = 7). Among the 9 evaluable pts with LMS, 0 achieved a PR, the DCR was 44.4% (4/9), median PFS was 3.9 months and 3 pts were still receiving treatment. In the overall cohort (n = 32), TRAEs of any grade occurred in 56.3% of pts (n = 18), the most common were myelosuppression (28.1%), fatigue (15.6%), fever (12.5%) and rash (12.5%). Grade 3/4 TRAEs occurred in 12.5% of pts, with no grade 5 events. Conclusions: This study demonstrates the potential efficacy of combination therapy with eribulin, an ICI and anlotinib in patients with advanced STS, especially in those with the DDLPS subtype. Our data suggest that this combination has good tolerability and a prospective trial is warranted. Clinical trial information: ChiCTR2100053594.

Gene expression-based prediction of pazopanib efficacy in sarcoma

BackgroundThe multi-receptor tyrosine kinase inhibitor pazopanib is approved for the treatment of advanced soft-tissue sarcoma and has also shown activity in other sarcoma subtypes. However, its clinical efficacy is highly variable, and no reliable predictors exist to select patients who are likely to benefit from this drug. Patients and methodsWe analysed the molecular profiles and clinical outcomes of patients with pazopanib-treated sarcoma enrolled in a prospective observational study by the German Cancer Consortium, DKTK MASTER, that employs whole-genome/exome sequencing and transcriptome sequencing to inform the care of young adults with advanced cancer across histology and patients with rare cancers. ResultsAmong 109 patients with available whole-genome/exome sequencing data, there was no correlation between clinical parameters, specific genetic alterations or mutational signatures and clinical outcome. In contrast, the analysis of a subcohort of 62 patients who underwent molecular analysis before pazopanib treatment and had transcriptome sequencing data available showed that mRNA levels of NTRK3 (hazard ratio [HR] = 0.53, p = 0.021), IGF1R (HR = 1.82, p = 0.027) and KDR (HR = 0.50, p = 0.011) were independently associated with progression-free survival (PFS). Based on the expression of these receptor tyrosine kinase genes, i.e. the features NTRK3-high, IGF1R-low and KDR-high, we developed a pazopanib efficacy predictor that stratified patients into three groups with significantly different PFS (p < 0.0001). Application of the pazopanib efficacy predictor to an independent cohort of patients with pazopanib-treated sarcoma from DKTK MASTER (n = 43) confirmed its potential to separate patient groups with significantly different PFS (p = 0.02), whereas no such association was observed in patients with sarcoma from DKTK MASTER (n = 97) or The Cancer Genome Atlas sarcoma cohort (n = 256) who were not treated with pazopanib. ConclusionA score based on the combined expression of NTRK3, IGF1R and KDR allows the identification of patients with sarcoma and with good, intermediate and poor outcome following pazopanib therapy and warrants prospective investigation as a predictive tool to optimise the use of this drug in the clinic.

The Role of Trabectedin in Soft Tissue Sarcoma.

Background: Systemic chemotherapy for advanced disease is another therapeutic option in the management of metastases in soft tissue sarcoma (STS). Doxorubicin either alone or in combination with ifosfamide has been used as first-line chemotherapy. Furthermore, in the past decade, new drugs have been shown to be effective in the treatment of advanced STS after the failure of first-line anthracycline-based chemotherapy: trabectedin, pazopanib and eribulin. However, the appropriate usage of these agents has not been established. Methods: We summarized clinical trials of trabectedin focusing on the efficacy and toxicity of trabectedin in the treatment of STS. Results: Trabectedin can be administered safely and effectively to the patients with advanced STS at second line setting or later. Although trabectedin may be effective as first-line treatment in selected patients, anthracycline-based chemotherapy should be recommended because no regimen in addition to trabectedin has proved to be unequivocally superior to doxorubicin as the first-line treatment for locally advanced or metastatic STS. Nucleotide excision repair (NER) and homologous recombination (HRe) repair may be of particular importance as efficacy of trabectedin. Conclusion: Trabectedin has shown a favorable toxicity profile and is an alternative therapeutic option in patients with advanced STS.

143P Novel anti-PD-L1 antibody TQB2450 (T) in combination with anlotinib (A) in patients with advanced soft tissue sarcoma (STS), the results from the expanded sample size and updated data

T is a novel anti-PD-L1 antibody and A is a multi-kinase inhibitor. This study aims to evaluate the efficacy and safety of T in combination with A in the treatment of advanced STS. Preliminary results had disclosed the potential of this regimen, here we report the results based on the expanded sample size and updated data.

1533P Gene expression-based prediction of pazopanib benefit in sarcomas

The multi-tyrosine kinase inhibitor pazopanib is approved for the treatment of advanced soft-tissue sarcoma and has also shown activity in other sarcoma subtypes. However, biomarkers to prospectively identify patients who will benefit from the drug are lacking.

Analysis of clinical factors associated with survival in patients with soft-tissue sarcoma receiving trabectedin.

Soft-tissue sarcomas (STSs) are a heterogeneous group of rare malignancies. Treatment for advanced STS usually starts with anthracycline-based therapies, with no clear sequence for further treatment. A preferred option is trabectedin, especially for liposarcoma and leiomyosarcoma (L-sarcoma). However, due to severe side effects and few clinical trials, further research of the parameters affecting survival is necessary for the optimal selection of patients. We retrospectively analyzed 73 consecutive patients with STS treated with trabectedin at the University Hospital Centers at Zagreb and Osijek from 2014 to 2021. Our primary goals were evaluating factors affecting progression-free survival (PFS) and overall survival (OS). The median PFS and OS for trabectedin were 3.6 months and 13.7 months, respectively. Patients with L-sarcoma exhibited longer PFS and a trend towards longer OS compared to those with non-L-sarcoma. However, these effects were primarily a result of the myxoid liposarcoma subtype, which exhibited a median PFS of 21.1 months and a median OS of 33.3 months, both significantly longer compared to non-myxoid L-sarcoma. Additionally, patients with three or more sites of metastases exhibited shorter median PFS (3.1 months vs. 3.6 months) and OS (5.7 months vs. 23.8 months) compared to only one metastatic site. There was no correlation between the PFS values of trabectedin and pazopanib and no difference in survival, regardless of the treatment sequence. Trabectedin treatment yields the greatest survival benefit in patients with myxoid liposarcoma and low metastatic burden, whereas the additional use of pazopanib provides further clinical benefit, regardless of treatment sequence.

Efficacy and safety of anlotinib combined with liposomal doxorubicin in first-line treatment of advanced soft-tissue sarcoma.

e23530 Background: Anthracycline-based chemotherapy is the main first-line treatment option for advanced soft-tissue sarcoma (STS). Anlotinib has been approved for the treatment of STS by the Chinese agency. This study was performed to evaluate the efficacy and safety of Anlotinib combined with liposomal doxorubicin in first-line treatment of patients with advanced STS. Methods: This is a single-center, retrospective study. Eligible patients were those ≥14 years old, ECOG performance state of 0-1, with histologically confirmed locally advanced, unresectable or metastatic STS, previously untreated, with measurable disease by RECIST v1.1. All patients received Anlotinib (12mg once daily, 2 weeks on and 1 week off) and liposomal doxorubicin (40-50 mg/m2, IV, D1, every 3 weeks) until disease progression or unacceptable adverse events. The primary endpoint was progression-free survival (PFS). Disease control rate (DCR), objective response rate (ORR), and side effects were also calculated. Results: Between April 2019 and December 2020, 8 patients were evaluated, including 2 undifferentiated pleomorphic sarcoma, 1 liposarcoma, 4 fibrosarcomas, and 1 synovial sarcoma. The median age was 42 years. 2 patients (25%) achieved a confirmed partial response (PR) and 3(37.5%) had stable disease (SD). The ORR and DCR were 25% and 62.5% respectively. The median PFS was 11.3 months, and the PFS rate at 4 months was 50%. Treatment-related adverse events included hand-foot syndrome (3/8, 37.5%), pneumothorax (1/8, 12.5%), oral mucositis (2/8, 25%), epistaxis (2/8, 25%), hypertension (2/8, 25%), arrhythmias (1/8, 12.5%), and pharyngeal pain (1/8, 12.5%). Three patients experienced grade 3 or 4 adverse events, 2 hand-foot syndrome (2/8, 25%) and 1 pneumothorax (1/8, 12.5%). Conclusions: This study suggested that the combination of Anlotinib and liposomal doxorubicin might have anti-tumor activity and acceptable toxicity in first-line treatment of patients with advanced STS.

Anlotinib as a molecular targeted therapy for tumors.

Angiogenesis has an essential role in tumor growth and metastasis, and blocking this pathway has been a successfully utilized strategy in the clinical treatment of cancer. Anlotinib (AL3818) is a novel oral receptor tyrosine kinase inhibitor targeting vascular endothelial growth factor receptor 2 and 3, fibroblast growth factor 1-4, platelet-derived growth factor receptor α and β, c-Kit and Ret. Anlotinib exerts inhibitory effects on tumor growth and angiogenesis and received its first approval as a third-line treatment for refractory advanced non-small-cell lung cancer in May 2018 and its second approval as a second-line treatment for advanced soft-tissue sarcoma in June 2019 in the People's Republic of China. Anlotinib has encouraging efficacy and a manageable and tolerable safety profile in a broad range of malignancies, including medullary thyroid cancer, renal cell cancer, gastric cancer and esophageal squamous cell carcinoma. In the present review, the preclinical and clinical trials of anlotinib were summarized with a focus on safety evaluation and adverse event management.

Immune-checkpoint genes as predictive biomarkers of trabectedin in advanced soft-tissue sarcoma (STS): A Spanish Group for Research on Sarcomas (GEIS) translational study.

11546 Background: Despite several second-line options are accessible for the treatment of advanced STS, there is a lack of predictive biomarkers available to support the rational selection of these drugs. Trabectedin specifically targets mononuclear cell lineage (macrophages and monocytes) that ultimately could inhibit tumor angiogenesis. Moreover, trabectedin seems to induce the expression of immune-checkpoint proteins (e.g. PD-L1); however, the predictive value of these factors remains unknown. We present the analyses of immune-checkpoint genes ( CD274, CD86, CTLA4, HAVCR2, LAG3 and PDCD1) and CD163, CD4, CD68 and CD8A expression as potential predictive factors of response to trabectedin in a subset of STS patients of the GEIS registry. Methods: Selection criteria included patients with STS, pretreated with at least 2 lines in the advanced setting (one line being trabectedin), with paraffin block available and ethic committee’s approval. Direct transcriptomics was performed using HTG Molecular Oncology Biomarker Pathway panel (HTG Molecular Diagnostics, Inc.; Tucson, AZ, USA), following manufacturers’ instructions. Data analyses were performed taking into account the median Log2 of expression of each gene and by correlating it with progression-free survival (PFS) for trabectedin, and overall survival measured from the starting date of trabectedin treatment (OS). Results: Among 387 registered patients, fitting with the inclusions criteria, 139 cases were used for gene expression analyses, as the discovery set. Patients had median age of 52 years, 54% were females and had a median follow-up from diagnosis of 44 months. High expression of CD274 (PD-L1) was significantly associated with better PFS of trabectedin (5.4 vs. 3.0 months; p= 0.006). Similar results were obtained with high expression of CTLA4 and LAG3: 6.0 vs 3.1 months; p = 0.005 and 5.4 vs 2.7 months; p = 0.042, respectively. Expression of CTLA4 and LAG3 showed no significant impact in OS; whereas CD274 high expression showed a trend towards better OS (17.9 vs 10.2 months; p = 0.077). Also, no significant correlation was achieved for CD163, CD4, CD68, CD8A, CD86 and HAVCR2; PDCD1 (PD-1) showed a trend towards better PFS of trabectedin, p = 0.114. Conclusions: The expression of selected immune-checkpoint genes exhibited a potential predictive value for trabectedin in advanced STS. Validation studies (at the transcriptional and protein level) are currently ongoing to confirm their potential predictive role.

Assessment of Safety and Efficacy of Combined Trabectedin and Low-Dose Radiotherapy for Patients With Metastatic Soft-Tissue Sarcomas

Active therapeutic combinations, such as trabectedin and radiotherapy, offer potentially higher dimensional response in second-line treatment of advanced soft-tissue sarcomas. Dimensional response can be relevant both for symptom relief and for survival. To assess the combined use of trabectedin and radiotherapy in treating patients with progressing metastatic soft-tissue sarcomas. Phase 1 of this nonrandomized clinical trial followed the classic 3 + 3 design, with planned radiotherapy at a fixed dose of 30 Gy (3 Gy/d for 10 days) and infusion of trabectedin at 1.3 mg/m2 as the starting dose, 1.5 mg/m2 as dose level +1, and 1.1 mg/m2 as dose level -1. Phase 2 followed the Simon optimal 2-stage design. Allowing for type I and II errors of 10%, treatment success was defined as an overall response rate of 35%. This study was conducted in 9 sarcoma referral centers in Spain, France, and Italy from April 13, 2015, to November 20, 2018. Adult patients with progressing metastatic soft-tissue sarcoma and having undergone at least 1 previous line of systemic therapy were enrolled. In phase 2, patients fitting inclusion criteria and receiving at least 1 cycle of trabectedin and the radiotherapy regimen constituted the per-protocol population; those receiving at least 1 cycle of trabectedin, the safety population. Trabectedin was administered every 3 weeks in a 24-hour infusion. Radiotherapy was required to start within 1 hour after completion of the first trabectedin infusion (cycle 1, day 2). The dose-limiting toxic effects of trabectedin (phase 1) and the overall response rate (phase 2) with use of trabectedin plus irradiation in metastatic soft-tissue sarcomas. Eighteen patients (11 of whom were male) were enrolled in phase 1, and 27 other patients (14 of whom were female) were enrolled in phase 2. The median ages of those enrolled in phases 1 and 2 were 42 (range, 23-74) years and 51 (range, 27-73) years, respectively. In phase 1, dose-limiting toxic effects included grade 4 neutropenia lasting more than 5 days in 1 patient at the starting dose level and a grade 4 alanine aminotransferase level increase in 1 of 6 patients at the +1 dose level. In phase 2, among 25 patients with evaluable data, the overall response rate was 72% (95% CI, 53%-91%) for local assessment and 60% (95% CI, 39%-81%) for central assessment. The findings of this study suggest that the recommended dose of trabectedin for use in combination with this irradiation regimen is 1.5 mg/m2. The trial met its primary end point, with a high overall response rate that indicates the potential of this combination therapy for achieving substantial tumor shrinkage beyond first-line systemic therapy in patients with metastatic, progressing soft-tissue sarcomas. ClinicalTrials.gov Identifier: NCT02275286.

Update on Systemic Therapy for Advanced Soft Tissue Sarcoma

Background: Soft tissue sarcoma (STS) is a rare group of mesenchymal neoplasms which contains over 50 heterogenous subtypes. There have been great efforts to increase the understanding of treatment of advanced STS (unresectable or metastatic disease). We wished to determine if outcomes for patients with advanced STS have improved over time, and to assess the current evidence for systemic therapy. Methods: We performed a scoping review to evaluate the contemporary evidence for systemic treatment of advanced soft tissue in adults (&gt;18 years old). Phase I, II, and III studies of systemic therapy for advanced STS published in the English language were included. After abstract and full text review of 77 studies, 62 trials met inclusion criteria. Results: The number of clinical trials conducted and published in advanced STS has increased over the last 30 years. Although median OS has increased, attempts at improving first line therapy through dose intensification, doublet chemotherapy or alternative backbones have not been successful. The optimal therapy beyond anthracyclines remains a challenge, especially given the inherent heterogeneity of grouping multiple STS subtypes within clinical trials. However, increasing numbers of agents are being studied and several studies had shown isolated PFS or OS benefit. Conclusions: First line anthracycline systemic therapy remains the standard of care for advanced STS. However, choice of subsequent therapy beyond anthracyclines remains challenging. Novel systemic therapies, using molecular diagnostics to direct therapy, subtype specific trials and learning from real world retrospective data are all important in improving outcomes for patients with advanced STS.

PCN316 TREATMENT PATTERNS OF ADVANCED SOFT-TISSUE SARCOMA IN ARGENTINA

To describe the treatment patterns of patients with advanced soft-tissue sarcomas who received chemotherapy or radiotherapy in Argentina. Patients with advanced soft-tissue sarcoma (locally advanced, inoperable, or metastatic disease) who received chemotherapy or radiotherapy from 2013-2018 were selected from the Instituto de Especialidades Médicas S.A. (IEMSA) clinical database, which collects the information of several insurance providers (Social Security System and Health Maintenance Organizations). Cases with osteosarcoma, Kaposi’s Sarcoma and gastrointestinal stromal tumors were excluded. A total of 99 patients were analysed. There was a high variability in histological type, with leiomyosarcoma (N=17; 17%), pleomorphic sarcoma (N=12; 12%), liposarcoma (N=10; 10%), and rhabdomyosarcoma (N=10; 10%) being the most frequent. The most frequent locations were leg (33%), abdomen (16%), and arm (14%). At the time of diagnosis, 46% of the cases were localized, 26% were loco-regionally advanced and 27% were metastatic. Of the 99 patients, 50.5% received adjuvant/neoadjuvant therapy, and of them, 50% received only chemotherapy, 30% received only adjuvant/neoadjuvant radiotherapy, and 20% received both therapies. There were 86 patients who received first-line therapy for metastatic disease. Seventy-nine percent of them received chemotherapy. The most frequent chemotherapy was doxorubicin-ifosfamide-mesna (N=22; 32%), and docetaxel-gemcitabine (N=6, 9%), and epirubicin-ifosfamide-mesna (N=3; 4%). There was a high variability in the rest of the treatments. During the first-line therapy, twenty-one patients (24%) had surgery, and fifteen patients (17%) received radiotherapy. Only one patient had a complete response after first-line chemotherapy. Forty-five patients received second-line therapy, 93% of whom received chemotherapy. Again, the most frequent treatments were doxorubicin-ifosfamide-mesna (N=13; 31%) and docetaxel-gemcitabine (N=9; 21%). Two patients experienced a complete response with second-line therapy. There is a high variability in the treatment of advanced soft-tissue sarcomas in Argentina. Response to current chemotherapy treatments is very poor. There is a large need for more effective treatments.

Safety and efficacy of olaratumab added to doxorubicin-based combination chemotherapy in the treatment of advanced soft-tissue sarcoma (STS).

e23542Background: Patients with advanced STS face a median overall survival of 12-16 months. Olaratumab (olara) in addition to doxorubicin (dox) showed survival advantage over single agent dox with...

Olaratumab: A New Strategy in the Treatment of Advanced Soft-Tissue Sarcoma

Olaratumab is a monoclonal antibody that recently received accelerated approval for the treatment of advanced soft-tissue sarcomas in combination with doxorubicin for a histologic subtype in which anthracycline-containing regimens is appropriate and disease is not amenable to curative surgery or radiotherapy. It inhibits platelet-derived growth factor receptor alpha, leading to the inhibition of tumor cell proliferation, angiogenesis, and metastasis. In a phase II clinical trial, olaratumab in combination with doxorubicin met its predefined primary endpoint of improving progression-free survival and secondary endpoint of overall survival compared to doxorubicin monotherapy in patients with advanced soft-tissue sarcoma. Common adverse events associated with the combination of olaratumab and doxorubicin include nausea, mucositis, neutropenia, and infusion-related reactions.

Developments in the management of advanced soft-tissue sarcoma - olaratumab in context.

Lartruvo® (olaratumab) is a fully human immunoglobulin G subclass 1 (IgG1) monoclonal antibody that inhibits platelet-derived growth factor receptor alpha (PDGFRα). The antitumor activity of olaratumab has been tested in vitro and in vivo, and inhibition of tumor growth has been observed in cancer cell lines, including glioblastoma and leiomyosarcoma cells. It represents the first-in-class antibody to be approved by regulatory authorities for the treatment of advanced soft-tissue sarcomas (STSs) in combination with doxorubicin, based on the results of the Phase Ib/II trial by Tap et al. The median progression-free survival (PFS), which was the primary end point of the study, was improved for patients treated with olaratumab plus doxorubicin compared to those treated with doxorubicin monotherapy (6.6 vs 4.1 months, respectively; HR 0.672, 95% CI 0.442–1.021, p=0.0615). Moreover, final analysis of overall survival (OS) showed a median OS of 26.5 months with olaratumab plus doxorubicin vs 14.7 months with doxorubicin, with a gain of 11.8 months (HR 0.46, 95% CI 0.30–0.71, p=0.0003). In October 2016, olaratumab was admitted in the Accelerated Approval Program by the US Food and Drug Administration (FDA) for use in combination with doxorubicin for the treatment of adult patients with STSs. In November 2016, the European Medicines Agency (EMA) granted conditional approval for olaratumab in the same indication under its Accelerated Assessment Program. A double-blind, placebo-controlled, randomized Phase III study (ANNOUNCE trial, NCT02451943) is being performed in order to confirm the survival advantage of olaratumab and to provide definitive drug confirmation by regulators. The study is ongoing, but enrollment is closed. The purpose of this review was to evaluate the rationale of olaratumab in the treatment of advanced STSs and its emerging role in clinical practice.

PP147 Olaratumab With Doxorubicin For Advanced Soft Tissue Sarcoma

Introduction:The National Institute for Health and Care Excellence (NICE) invited the manufacturer of olaratumab (Lartruvo®), Eli Lilly &amp; Company Limited, to submit evidence for the clinical and cost effectiveness of this drug, in combination with doxorubicin, for advanced soft tissue sarcoma (STS) not amenable to surgery or radiotherapy, as part of the Institute's Single Technology Appraisal. The Peninsula Technology Assessment Group critically reviewed the submitted evidence.Methods:Clinical effectiveness was derived from an open-label, randomized controlled trial, JGDG. The economic analysis was based on a partitioned survival model with a time horizon of 25 years. The perspective was of the UK National Health Service (NHS) and Personal Social Services. Costs and benefits were discounted at 3.5 percent per year. The company's evidence was submitted in anticipation that olaratumab would be considered as an alternative to doxorubicin, which has been used as a first-line treatment for advanced STS. To improve the cost effectiveness of olaratumab, the company offered a discount through a Commercial Access Agreement with the NHS England.Results:In the company's submission, the mean base-case and probabilistic incremental cost-effectiveness ratios (ICERs) for olaratumab plus doxorubicin versus doxorubicin alone were GBP 46,076 (USD 61,403) and GBP 47,127 (USD 62,804) per quality-adjusted life-year (QALY) gained, respectively; the probability of this treatment being cost effective at the willingness-to-pay threshold of GBP 50,000 (USD 66,632) per QALY gained, applicable to end-of-life treatments, was 0.54. The respective estimates in our analysis were approximately GBP 60,000 (USD 79,959) per QALY gained, and the probability of cost-effectiveness was 0.21. The increase in the ICERs was primarily due to differences in extrapolation of overall survival, and drug administration costs.Conclusions:Based on the available evidence, olaratumab in combination with doxorubicin improves the survival of patients with advanced STS. However, this treatment is unlikely to be cost-effective. Olaratumab is now recommended for use within the Cancer Drugs Fund.

Pharmacokinetic drug evaluation of pazopanib for the treatment of uterine leiomyosarcomas

ABSTRACTIntroduction: Uterine leiomyosarcomas (ULMS) represent 1.3% of all uterine malignant tumors. Surgery is the curative treatment for patients with early stage disease. In case of advanced, persistent or recurrent tumor, chemotherapy represents the standard of care, but these patients have a poor prognosis. As the results with available therapies are far from being satisfactory, research is focusing on identification of new compounds. In 2012 the Food and Drug Administration (FDA) licensed pazopanib for the treatment of advanced soft-tissue sarcomas failing previous chemotherapy.Areas covered: The aim of this article is to review the literature on the pharmacokinetics, pharmacodynamics, clinical efficacy and safety of the tyrosine kinase inhibitor (TKI), pazopanib in the treatment of ULMS.Expert opinion: The discovery of some relevant signalling pathways in LMS cells led to the development of new targeted drugs with promising results in the management of these tumors. Pazopanib is a multi-target second-generation TKI with activity against growth factors involved in angiogenesis. It has shown promising results both in terms of efficacy and safety, as shown in the EORTC 62043 Study and the PALETTE trial. Further studies are awaited to evaluate its efficacy in uterine leiomyosarcomas.

Predictive role of FAS for trabectedin in second lines of advanced soft tissue sarcoma (ASTS): A Spanish group for research on sarcoma (GEIS) study.

11071 Background: There are currently several second-line options for the treatment of ASTS as gemcitabine combinations, trabectedin, pazopanib, eribulin or olaratumab plus doxorubicin in cases where anthracyclins are still possible. There is an unmet need for predictive biomarkers which hinders the rational selection of the best sequence in second line. We already published the prognostic value of FAS in first line of ASTS while this study analyzes its predictive role in different second line schemes. Methods: Most relevant selection criteria for this study were having received trabectedin in 2nd line or beyond for ASTS, progressive disease after at least one previous line for ASTS and signed CI. A TMA was set up for FAS staining (Cell Signaling) with blocks from diagnostic time. Two expert blinded pathologists reviewed and classified the cases as negative, weak or strong. Kaplan–Meier estimations were used for time-to-event variables and the log-rank test was used to compare groups. Results: A series of 198 patients accomplished selection criteria. Metastases at diagnosis occurred in 46 (24%) and median time to metastases was 18.8 months (CI 16,3; 21.3). Previous line to trabectedin consisted of gemcitabine combination 83 (42%), Doxorubicin-based 65 (33%) and others 50 (25%). Median PFS for previous and trabectedin lines were 3.5 (2.8-4.2) and 3.4 (2.8-4) months respectively. FAS positive entailed significantly better PFS for the previous trabectedin line: 4.1 (1.5-6.7) vs 3.0 (2.5-3.5) months, p = 0.01 whereas FAS positive was related with worse PFS for the trabectedin line 2.5 (2.2-2.8) vs 3.7 (2.7-4.8) months, p = 0.028. These results were more notorious for L-sarcoma cases: 7.0 (3.6-10.5) vs 4.3 (1.9-6.6) months, p = 0.017 in previous line and 2.4 (2.2-2.6) vs 6.5 (3.8-9.3) months, p &lt; 0.001 in trabectedin. From trabectedin administration, FAS+ had significantly worse OS especially in L-sarcomas: 11.9 (5.2-18.7) vs 21.7 (12.7-30.8) months, p = 0.002. Conclusions: FAS showed predictive value in PFS and OS for trabectedin administration in ASTS. The different prognostic role of FAS across distinct lines and its relevance in L-sarcomas deserve further attention.

Trabectedin for advanced soft-tissue sarcoma: A single-center experience of over 10 years.

11052Background: Trabectedin (T) is an anti-tumor agent used in the treatment of advanced soft-tissue sarcomas (STS). It interferes with DNA replication, causing double strand breaks and apoptosis,...

A phase Ib dose-escalation study of TRC105 (anti-endoglin antibody) in combination with pazopanib in patients with advanced soft tissue sarcoma (STS).

10514 Background: The VEGFR inhibitor pazopanib is approved for the treatment of advanced STS. Resistance to pazopanib is a challenge in the treatment of STS, and endoglin (CD105) activation may be an important resistance mechanism. Endoglin is an angiogenic receptor expressed on proliferating tumor vessels, which is upregulated following VEGF inhibition and expressed on certain STS subtypes, including angiosarcoma. A phase Ib study of TRC105, an anti-endoglin antibody, in combination with pazopanib was performed in patients (pts) with advanced STS. Methods: Heavily-pretreated STS pts with leiomyosarcoma (11); angiosarcoma (2); synovial sarcoma (2); epithelioid sarcoma (1); myxofibrosarcoma (1); epithelioid hemangioendothelioma (1); and unclassifiable high grade sarcoma (2), ECOG PS 0-1, were treated with infusional TRC105 weekly in two cohorts (8mg/kg and 10mg/kg). TRC105 was initiated following a 2 to 4 week lead-in period of pazopanib starting at 800 mg PO daily. Results: Twenty pts (median age = 57; M...