A molecular signature predictive of clinical outcome following pazopanib therapy in advanced soft tissue sarcoma
Paul H. HuangA. LeeFrank McCarthyKhin ThwayJames P. MordenChristina MessiouFrances DaleyRichard BuusCyril FisherMaggie C.U. CheangIan JudsonRobin L. Jones
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Pazopanib
Trabectedin
Progression-free survival
Tissue microarray
11068 Background: Roughly 10% of patients with soft tissue sarcoma (STS) present with synchronous metastases and generally cannot be cured anymore. With the registration of trabectedin, pazopanib and the identification of other agents exerting activity against STS, the treatment of these patients in the Netherlands has changed considerably in the last decade. The aim of this population-based study is to examine whether the overall survival (OS) of patients with STS and synchronous metastases has improved over the years. Methods: All patients diagnosed with adult-type STS and synchronous metastases between 1989 and 2014 were queried from the Netherlands Cancer Registry. Trends in OS were assessed by the Kaplan Meier method and log rank test in different timeframes based on year of registration of trabectedin ( < 2007 vs. ≥2007) and pazopanib ( < 2012 vs. ≥2012). A multivariable Cox regression analysis was performed to identify relevant characteristics prognostic for OS. Results: In total, 1,393 patients with adult-type STS and synchronous metastases were identified. Over the whole time period, median OS did not improve significantly (5.8 months in 1989-1994 to 8.1 months in 2010-2014, p = 0.095), but median OS < 2007 compared to ≥2007 did improve significantly (5.8 months to 7.3 months, p = 0.035). This was particularly apparent in the liposarcoma subgroup, where median OS doubled (5.2 months to 11.5 months, p = 0.020). Median OS < 2012 compared to ≥2012 did not increase significantly (6.1 months to 7.6 months, p = 0.062), though there was a relatively short follow-up of 2 years while the survival curve seems to reach a plateau phase. Aside from not receiving (any type of) treatment, elderly age, STS subtype other than lipo- or leiomyosarcoma, high or unknown grade and nodal involvement were significant negative predictors for OS, whereas primary tumor site in the extremity and surgery in an academic center had a favorable effect on OS. Conclusions: OS of STS patients with synchronous metastases has not improved significantly over the years, except for the subgroup of liposarcomas after 2007. A longer follow-up period is needed to clarify the impact of pazopanib on OS in patients with metastatic STS.
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e23555 Background: Soft tissue sarcomas (STS) are rare tumors with more than 50 histologic subtypes. Treatment outcomes for patients with STS has improved over the past few decades mostly due to the adoption of a multidisciplinary approach, but still patients with advanced disease have a poor prognosis.Our study compared efficacy of novel sarcoma therapies - pazopanib and trabectedin vs standard chemotherapy, after failure to anthracycline based therapy,in patients with metastatic STS, Methods: In the period between 2014 and 2017 we made a retrospective analysis of 80 patients treated in Clinical Centre University of Sarajevo and University Hospital Centre Zagreb for metastatic STS. All patients received antracycline based therapy as a first line therapy. Patients were grouped in two cohorts. Patients in first cohort received pazopanib and/or trabectedin as a 2nd line treatment. In second cohort patients were treated with standard chemotherapy protocols. Efficacy was assessed in terms of RR(response rate) and PFS(progression free survival). Results: For patients treated with pazopanib PFS in 2nd line therapy was 4.6 months and for trabectidine group 6.15 months. Patients receiving standard chemotherapy as a 2nd line treatment had PFS of 2.0 months. Conclusions: Doxorubicin monotherapy is currently the only standard option for the first-line treatment of STS. For second-line and subsequent lines of treatment, there is no standard therapy. Results of our study confirmed superior efficacy of novel therapies pazopanib and trabectedin over standard chemotherapy. Our results are in correlation with results of pivotal trials (PALETTE and ET743-SAR-3007 trial) for pazopanib and trabectedin. Future clinical trials should adress issues such as sequential therapy, identification of biomarkers and the use of immunotherapy in sarcoma treatment.Clinical studies exploring efficacy of novel drugs in specific histologies are needed.
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Background: This study examined the efficacy/effectiveness of pazopanib and trabectedin in previously treated metastatic synovial sarcoma (mSS). Materials & methods: A literature search identified studies (2002–2019) reporting outcomes of pazopanib and trabectedin in previously treated mSS, including median overall survival (mOS) and overall response rate (ORR). A meta-analysis was conducted and sensitivity analyses examined outcomes by agent (pazopanib/trabectedin), study type (clinical trial [CT] or real-world [RW]) and sample size. Results: Sixteen studies were included (pazopanib: n = 7; trabectedin: n = 9). Pooled mOS was 10.4 months and was consistent across agents and in RW and CT (pazopanib: 10.3; trabectedin: 10.4; CT: 10.8; RW: 9.9). ORR results were more variable (pooled ORR: 14.7%). ORR was consistently higher for RW (17.7%) than for CT (9.5%) and for pazopanib (18.9%) compared with trabectedin (12.3%). Conclusion: Poor outcomes across agents and settings highlight a need for novel treatments with improved efficacy. This study serves as a benchmark for efficacy estimates in this rare disease.
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Abstract Background Alveolar soft part sarcoma (ASPS) is an exceedingly rare and orphan disease, without active drugs approved in the front line. Pazopanib and trabectedin are licensed for sarcoma treatment from second-line, but very little and contradictory data are available on their activity in ASPS. Lacking ongoing and/or planned clinical trials, we conducted a multi-institutional study involving the reference sites for sarcoma in Europe, U.S., and Japan, within the World Sarcoma Network, to investigate the efficacy of pazopanib and trabectedin. Materials and Methods From May 2007, 14 of the 27 centers that were asked to retrospectively review their databases had identified 44 advanced ASPS patients treated with pazopanib and/or trabectedin. Response was evaluated by Response Evaluation Criteria in Solid Tumors 1.1. Progression-free survival (PFS) and overall survival (OS) were computed by Kaplan-Meier method. Results Among 30 patients who received pazopanib, 18 were pretreated (13 with other antiangiogenics). Response was evaluable in 29/30 patients. Best responses were 1 complete response, 7 partial response (PR), 17 stable disease (SD), and 4 progressions. At a 19-month median follow-up, median PFS was 13.6 months (range: 1.6–32.2+), with 59% of patients progression-free at 1 year. Median OS was not reached. Among 23 patients treated with trabectedin, all were pretreated and evaluable for response. Best responses were 1 PR, 13 SD, and 9 progressions. At a 27-month median follow-up, median PFS was 3.7 months (range: 0.7–109), with 13% of patients progression-free at 1 year. Median OS was 9.1 months. Conclusion The value of pazopanib in advanced ASPS is confirmed, with durable responses, whereas the value of trabectedin appears limited. These results are relevant to defining the best approach to advanced ASPS. Implications for Practice This retrospective study, conducted among the world reference centers for treatment of sarcoma, confirms the value of pazopanib in patients with advanced alveolar soft part sarcoma (ASPS), with dimensional and durable responses, whereas trabectedin shows a limited activity. Alveolar soft part sarcoma is resistant to conventional cytotoxic chemotherapy. Pazopanib and trabectedin are licensed for treatment of sarcoma from second line; in the lack of prospective clinical trials, these results are relevant to defining ASPS best management and strongly support initiatives aimed at obtaining the approval of pazopanib in the front line of the disease.
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Introduction: Soft tissue sarcoma accounts for less than 1% of all malignant neoplasms and is comprised of a very heterogeneous group of tumors with over 50 different subtypes.Due to its diversity and rarity, developing new therapeutics has been difficult, at best.The standard of care in the treatment of advanced and metastatic disease over the last 30 years has been doxorubicin and ifosfamide, either alone or in combination.There has been significant focus on developing new therapeutics to treat primary and metastatic disease.Trabectedin (ecteinascidin-743) is a tetrahydroisoquinoline alkaloid which has been evaluated in the treatment of metastatic soft tissue sarcoma.Aims: To review the current evidence for the therapeutic use of trabectedin in patients with soft tissue sarcoma.Evidence review: Five phase I studies in patients with solid tumors, all of which include sarcoma patients, evaluating the dosing and toxicity of trabectedin were performed with efficacy being evaluated as a secondary endpoint.Additionally, there are four phase I trials evaluating trabectedin in combination with frontline therapeutic drugs in soft tissue sarcoma.Four phase II studies were performed in soft-tissue sarcoma patients with objective response rates ranging from 3.7% to 17.1%.Additionally, in two compassionate use trials, objective response rates between 14% and 51% were seen, the largest response resulting from a study specifically focusing on liposarcoma.Place in therapy: Trabectedin is a potential therapeutic option for the management of softtissue sarcoma.It appears to have specific activity in a select group of histologies, most notably myxoid/round cell liposarcoma.Although it would be helpful to study the use of trabectedin in a randomized, controlled fashion, the relative rarity of soft-tissue sarcoma, and heterogeneity of the histologic subtypes, makes phase III trials a difficult prospect.
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Pazopanib, trabectedin, and eribulin are administered for the treatment of soft tissue sarcomas (STSs); however, there is little consensus on which agent should be preferentially used in a clinical setting. This study assessed whether peripheral immune-related markers served as a useful reference when selecting pazopanib, trabectedin, or eribulin. This study included 63 patients who were administered pazopanib, trabectedin, or eribulin for advanced STSs between March 2015 and December 2020. Patients were divided into three groups based on the first drug administered among these three drugs. Differences in overall survival (OS) or progression-free survival (PFS) among the three groups were analyzed. OS showed no significant differences among the drugs administered first. For patients with low neutrophil-to-lymphocyte ratio (NLR), the OS of patients administered pazopanib as the first choice was shorter than the others (hazard ratio [HR] = 9.53, 95% confidence interval [CI] = 1.94-18.13, p = 0.0018). In the low platelet-to-lymphocyte ratio (PLR) subgroup, the OS of the patients administered eribulin for the first choice was longer than that of the others (HR = 0.32, 95%CI = 0.10-0.98, p = 0.046). Therefore, NLR and PLR might be used as prognostic indicators to dictate whether STS patients receive pazopanib, trabectedin, or eribulin.
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Soft tissue sarcoma (STS) is a rare tumor with more than 50 histologic subtypes. Although treatment outcomes for patients with STS have improved greatly over the past few decades owing to the adoption of a multidisciplinary approach, patients with advanced disease have a poor prognosis. The development of anticancer drugs has been directed toward improving overall survival (OS). Doxorubicin monotherapy is currently the only standard option for the first-line treatment of STS. However, there is no standard therapy for second-line and later treatment at present. Since 2012, three anticancer drugs-pazopanib, trabectedin, and eribulin-have been approved in Japan for the second-line or later treatment of patients with advanced STS of any histologic subtype. However, the chemosensitivity of STS to each of these drugs varies by histologic subtype and their safety profiles differ; thus, histologic subtype and patient characteristics must be considered when determining optimal treatment. In this article, we review data from clinical studies related to the efficacy of all three drugs, including their effect on OS, and propose optimal treatment strategies for advanced STS by histologic subtype. In addition, with regard to the safety profiles, we highlight the key issues to be considered when selecting patients for treatment with pazopanib, trabectedin, or eribulin and ensuring their appropriate use, based on our combined clinical experience as specialists in the treatment of patients with STS. The proposed treatment strategies as well as treatment precautions based on clinical experience would benefit patients by maximizing the therapeutic effects and enhancing the proper use of these drugs.Eisai Co., Ltd.
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