Targeted treatment for advanced soft tissue sarcoma: profile of pazopanib.
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ABSTRACT:
SUBMITTER: Rajendra R
PROVIDER: S-EPMC3604972 | biostudies-literature | 2013
REPOSITORIES: biostudies-literature
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Targeted treatment for advanced soft tissue sarcoma: profile of pazopanib.
Rajendra Rajeev R Jones Robin L RL Pollack Seth M SM
OncoTargets and therapy 20130318
Soft tissue sarcomas comprise approximately 1% of all adult solid malignancies. While chemotherapy is the mainstay of treatment for patients with metastatic or inoperable disease, overall survival for these patients is approximately 12 months, highlighting the need for novel agents. Both laboratory and clinical data have suggested that antiangiogenic agents may have a role in the treatment of soft tissue sarcomas. Pazopanib is a multitargeted receptor tyrosine kinase inhibitor with antiangiogeni ...[more]
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Project description:BackgroundIn the phase iii palette trial of pazopanib compared with placebo in patients with advanced or metastatic soft-tissue sarcoma (sts) who had received prior chemotherapy, pazopanib treatment was associated with improved progression-free survival (pfs). We used an economic model and data from palette and other sources to evaluate the cost-effectiveness of pazopanib in patients with advanced sts who had already received chemotherapy.MethodsWe developed a multistate model to estimate expected pfs, overall survival (os), lifetime sts treatment costs, and quality-adjusted life-years (qalys) for patients receiving pazopanib or placebo as second-line therapy for advanced sts. Cost-effectiveness was calculated alternatively from the health care system and societal perspectives for the province of Quebec. Estimated pfs, os, incidence of adverse events, and utilities values for pazopanib and placebo were derived from the palette trial. Costs were obtained from published sources.ResultsCompared with placebo, pazopanib is estimated to increase qalys by 0.128. The incremental cost of pazopanib compared with placebo is CA$20,840 from the health care system perspective and CA$15,821 from the societal perspective. The cost per qaly gained with pazopanib in that comparison is CA$163,336 from the health care system perspective and CA$124,001 from the societal perspective.ConclusionsCompared with placebo, pazopanib might be cost-effective from the Canadian health care system and societal perspectives depending on the threshold value used by reimbursement authorities to assess novel cancer therapies. Given the unmet need for effective treatments for advanced sts, pazopanib might nevertheless be an appropriate alternative to currently used treatments.
| S-EPMC4257119 | biostudies-literature
Project description:In the phase III PALETTE trial, pazopanib improved progression-free survival (PFS) compared with placebo in patients with advanced/metastatic soft tissue sarcomas (mSTS) who had received prior chemotherapy. We used a multistate model to estimate expected PFS, overall survival (OS), lifetime STS treatment costs, and quality-adjusted life-years (QALYs) for patients receiving pazopanib, placebo, trabectedin, ifosfamide, or gemcitabine plus docetaxel as second-line mSTS therapies. The cost-effectiveness of pazopanib was expressed as the incremental costs per QALY gained. Estimates of PFS/OS, adverse events, and utilities for pazopanib and placebo were from the PALETTE trial. Estimates of relative effectiveness of the other comparators were from an unadjusted indirect comparison versus pazopanib. Costs were from published sources. Pazopanib is estimated to increase QALYs by 0.128 and costs by £7,976 versus placebo; cost per QALY gained with pazopanib versus placebo is estimated to be £62,000. Compared with the other chemotherapies, pazopanib provides similar QALYs at a lower cost. Pazopanib may not be cost-effective versus placebo but may be cost-effective versus the most commonly used active treatments, although this conclusion is uncertain. Given the unmet need for effective treatments for mSTS, pazopanib may be an appropriate alternative to some currently used medications in the United Kingdom.
| S-EPMC4082932 | biostudies-literature
Project description:Pazopanib is the first and only tyrosine kinase inhibitor currently approved for the treatment of multiple histological subtypes of soft tissue sarcoma (STS). Initially developed as a small molecule inhibitor of vascular endothelial growth factor receptors, preclinical work indicates that pazopanib exerts an anticancer effect through the inhibition of both angiogenic and oncogenic signaling pathways. Following the establishment of optimal dosing and safety profiles in early phase studies and approval for the treatment of advanced renal cell carcinoma, pazopanib was investigated in STS. A landmark phase III randomized study demonstrated improved progression-free survival with pazopanib compared to that with placebo in pretreated patients with STS of various subtypes. The efficacy of pazopanib in specific STS subtypes has been further described in real-world-based case series in both mixed and subtype-specific STS cohorts. At present, there are no clinically validated predictive biomarkers for use in selecting patients with advanced STS for pazopanib therapy, limiting the clinical effectiveness and cost-effectiveness of the drug. In this review, we summarize the preclinical and clinical data for pazopanib, outline the evidence base for its effect in STS and explore reported studies that have investigated putative biomarkers.
| S-EPMC6522548 | biostudies-literature
Project description:Soft tissue sarcomas are a form of rare and heterogeneous neoplasms with high recurrence rate and mortality. Over the past decades, less progress has been achieved. Surgical management with or without adjuvant/neoadjuvant radiotherapy is still the first-line treatment for localized soft tissue sarcomas, and chemotherapy is the additional option for those with high-risk. However, not all patients with advanced or metastatic soft tissue sarcomas benefit from conventional chemotherapy, targeted therapy takes the most relevant role in the management of those resistant to or failed to conventional chemotherapy. Heterogeneous soft tissue sarcomas vary from biological behavior, genetic mutations, and clinical presentation with a low incidence, indicating the future direction of histotype-based even molecule-based personalized therapy. Furthermore, increasing preclinical studies were carried out to investigate the pathogenesis and potential therapeutic targets of soft tissue sarcomas and increasing new drugs have been developed in recent years, which had started opening new doors for clinical treatment for patients with advanced/metastatic soft tissue sarcomas. Here we sought to summarize the concise characteristics and advance in the targeted therapy for the most common subtypes of soft tissue sarcomas.
| S-EPMC8727831 | biostudies-literature
Project description:BackgroundPALETTE is a phase 3 trial that demonstrated single-agent activity of pazopanib in advanced soft tissue sarcomas (aSTS). We performed retrospective subgroup analyses to explore potential relationships between patient characteristics, prior lines of therapy, dose intensity, and dose modifications on safety and efficacy of pazopanib in aSTS.MethodsPALETTE compared pazopanib with placebo in patients with aSTS (age ≥ 18 years) whose disease had progressed during or following prior chemotherapy. In these subgroup analyses, median progression-free survival (mPFS) among patients receiving pazopanib was the efficacy outcome of interest. Adverse events (AEs) were also compared within subgroups. All analyses were descriptive and exploratory.ResultsA total of 246 patients received pazopanib in the PALETTE study. The mPFS was longer in patients who had only 1 prior line versus 2+ prior lines of therapy (24.7 vs 18.9 weeks, respectively); AE rates were similar regardless of number of prior lines of therapy. The mPFS was similar in patients aged < 65 and ≥ 65 y (20.0 and 20.1 weeks, respectively). Although AEs leading to study discontinuation were higher in older patients (≥65 y, 30%; < 65 y, 17%), rates of dose reductions, dose interruptions, and serious AEs were similar between the 2 age groups. No reduction in mPFS was noted in patients requiring dose reductions or dose interruptions to manage toxicities.ConclusionsLonger mPFS was observed in patients receiving pazopanib following only 1 line of therapy. Additionally, mPFS with pazopanib was maintained regardless of patient age or dose modifications used to manage toxicity.Trial registrationNCT00753688 , first posted September 16, 2008 (registered prospectively).
| S-EPMC6691522 | biostudies-literature
Project description:PurposeEven though pazopanib, a multitargeted tyrosine kinase inhibitor, has been approved for refractory soft tissue sarcoma (STS), little is known about the molecular determinants of the response to pazopanib. We performed integrative molecular characterization to identify potential predictors of pazopanib efficacy.Materials and methodsWe obtained fresh pre-treatment tumor tissue from 35 patients with advanced STS receiving pazopanib-based treatment. Among those, 18 (51.4%) received pazopanib monotherapy, and the remaining 17 (48.6%) received pazopanib in combination with durvalumab, programmed death-ligand 1 blockade. Whole-exome and transcriptome sequencing were performed for each tumor and patient germline DNA.ResultsOf the 35 patients receiving pazopanib-based treatment, nine achieved a partial response (PR), resulting in an objective response rate (ORR) of 27.3%, and the median progression-free survival (PFS) was 6.0 months. Patients with CDK4 amplification (copy ratio tumor to normal > 2) exhibited shorter PFS (3.7 vs. 7.9 months, p=2.09×10-4) and a poorer response (ORR; 0% vs. 33.3%) compared to those without a gene amplification (copy ratio ≤ 2). Moreover, non-responders demonstrated transcriptional activation of CDK4 via DNA amplification, resulting in cell cycle activation. In the durvalumab combination cohort, seven of the 17 patients (41.2%) achieved a PR, and gene expression analysis revealed that durvalumab responders exhibited high immune/stromal cell infiltration, mainly comprising natural killer cells, compared to non-responders as well as increased expression of CD19, a B-cell marker.ConclusionDespite the limitation of heterogeneity in the study population and treatment, we identified possible molecular predictors of pazopanib efficacy that can be employed in future clinical trials aimed at evaluating therapeutic strategies.
| S-EPMC10101793 | biostudies-literature
Project description:Soft tissue sarcomas are rare malignant tumors derived from mesenchymal cells that have a high morbidity and mortality related to frequent occurrence of advanced and metastatic disease. Over the past two decades there have been significant advances in the use of targeted therapies for the treatment of soft tissue sarcoma. The ability to study various cellular markers and pathways related to sarcomagenesis has led to the creation and approval of multiple novel therapies. Herein, we describe the current landscape of targeted medications used in the management of advanced or metastatic soft tissue sarcomas, excluding GIST. We distinguish three categories: targeted therapies that have current US Food and Drug Administration (FDA) approval for treatment of soft tissue sarcoma, non-FDA approved targeted therapies, and medications in development for treatment of patients with soft tissue sarcoma.
| S-EPMC10034045 | biostudies-literature
Project description:BackgroundAlveolar 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 methodsFrom 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.ResultsAmong 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.ConclusionThe 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 practiceThis 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.
| S-EPMC5759809 | biostudies-literature
Project description:Therapy of soft tissue sarcomas represents an area of significant unmet need in oncology. Angiogenesis has been explored as a potential target both preclinically and clinically, with suggestions of activity. Pazopanib is a multitargeted tyrosine kinase inhibitor with prominent antiangiogenic effects. In a Phase II study, pazopanib demonstrated activity in strata enrolling patients with leiomyosarcomas, synovial sarcomas, or other sarcomas but not those enrolling adipocytic sarcomas. PALETTE, the pivotal Phase III trial, demonstrated improved progression-free survival versus placebo in pazopanib-treated patients previously treated for advanced soft tissue sarcomas. No survival benefit was observed, and adipocytic sarcomas were excluded. Health-related quality-of-life assessments indicated significant decrements in several areas affected by pazopanib toxicities, but no global deterioration. Cost-effectiveness analyses indicate that pazopanib therapy may or may not be cost-effective in different geographic settings. Pazopanib provides important proof-of-concept for antiangiogenic therapy in soft tissue sarcomas. Its use can be improved by further biological studies of its activity profile in sarcomas, studies of biological rational combinations, and clinicopathologic/biological correlative studies of activity to allow better drug targeting.
| S-EPMC4907704 | biostudies-literature
Project description:Soft-tissue sarcomas (STS) are a heterogeneous group of rare solid tumors of mesenchymal origin. This paper reviews the current status of systemic treatment in advanced and metastatic soft tissue sarcomas, with an emphasis on trabectedin. Trabectedin is a unique type of chemotherapeutic agent with multiple potential mechanisms of action. We discuss the putative mechanisms, as well as the toxicity and administration schedules of trabectedin, followed by its efficacy in first-line systemic therapy and beyond first-line systemic therapy.
| S-EPMC4993282 | biostudies-literature