Pazopanib, a Multikinase Angiogenesis Inhibitor, in Patients With Relapsed or Refractory Advanced Soft Tissue Sarcoma: A Phase II Study From the European Organisation for Research and Treatment of Cancer–Soft Tissue and Bone Sarcoma Group (EORTC Study 62043) (original) (raw)
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Pazopanib in advanced soft tissue sarcomas
Signal Transduction and Targeted Therapy, 2019
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.
Acta Oncologica, 2016
Background: Pazopanib is a multitargeted tyrosine kinase inhibitor approved for the treatment of patients with selective subtypes of advanced soft tissue sarcoma (STS) who have previously received standard chemotherapy including anthracyclines. Data on the efficacy in vascular sarcomas are limited. The main objective of this study was to investigate the activity of pazopanib in vascular sarcomas. Patients and methods: A retrospective study of patients with advanced vascular sarcomas, including angiosarcoma (AS), epithelioid hemangioendothelioma (HE) and intimal sarcoma (IS) treated with pazopanib in real life practice at EORTC centers as well as patients treated within the EORTC phase II and III clinical trials (62043/62072) was performed. Patient and tumor characteristics were collected. Response was assessed according to RECIST 1.1. and survival analysis was performed. Results: Fifty-two patients were identified, 40 (76.9%), 10 (19.2%) and two (3.8%) with AS, HE and IS, respectively. The response rate was eight (20%), two (20%) and two (100%) in the AS, HE and IS subtypes, respectively. There was no significant difference in response rate between cutaneous and noncutaneous AS and similarly between radiation-associated and non-radiation-associated AS. Median progression-free survival (PFS) and median overall survival (OS; from commencing pazopanib) were three months (95% CI 2.1-4.4) and 9.9 months (95% CI 6.5-11.3) in AS, respectively. Conclusion: The activity of pazopanib in AS is comparable to its reported activity in other STS subtypes. In this study, the activity of pazopanib was similar in cutaneous/non-cutaneous and in radiation/ non-radiation-associated AS. In addition, pazopanib showed promising activity in HE and IS, worthy of further evaluation.
Cancer, 2016
BACKGROUND: Because the efficacy and safety of pazopanib in Japanese patients with soft tissue sarcoma (STS) had not been evaluated previously in a large-scale cohort, the authors investigated the efficacy and safety of pazopanib in 156 Japanese patients with relapsed STS. This was a retrospective study based on the collection of real-life, postmarketing surveillance data. METHODS: Patients received pazopanib with the objective of treating local recurrence (n 5 20), metastasis (n 5 104), and both (n 5 32). The patient median age was 53.8 years. The primary objective of this study was to clarify the efficacy of pazopanib for patients with STS. RESULTS: The median treatment duration was 28.7 weeks, and the average dose intensity of pazopanib was 609 mg. Adverse events occurred in 127 patients (81.4%). In addition to the main common toxicities, such as hypertension and liver disorder, pneumothorax (n 5 11) and thrombocytopenia (n 5 16) also were observed. The median progression-free survival for all patients was 15.4 weeks. The median progression-free survival for patients with leiomyosarcoma, synovial sarcoma, undifferentiated pleomorphic sarcoma, and liposarcoma was 18.6 weeks, 16.4 weeks, 15.3 weeks, and 8 weeks, respectively. The median survival for all patients was 11.2 months. The median survival for patients with leiomyosarcoma, synovial sarcoma, undifferentiated pleomorphic sarcoma, and liposarcoma was 20.1 months, 10.6 months, 9.5 months, and 7.3 months, respectively. CONCLUSIONS: There were apparent differences in the efficacy of pazopanib treatment among histologic types of STS. Pazopanib treatment is a new treatment option; however, adverse events like pneumothorax and thrombocytopenia, which did not occur frequently in the PALETTE study (pazopanib for metastatic soft-tissue sarcoma), should be taken into consideration.
Annals of Surgical Oncology, 2019
Background. Preoperative devascularization might improve local control and thus the outcome of patients with soft tissue sarcoma (STS). The multikinase inhibitor pazopanib has antiangiogenic effects and is approved for treating metastatic STS. We conducted a trial of preoperative pazopanib therapy in high-risk STS. Methods. This single-arm, phase II trial included patients with resectable, non-metastatic, treatment-naïve, high-risk STS. Patients received pazopanib 800 mg daily while waiting for surgery (21-day 'window of opportunity'). The primary endpoint was metabolic response rate (MRR; proportion of patients with C 50% reduction of mean standardized uptake value [SUV mean ] in post-vs. pretreatment fluorodeoxyglucose-positron emission tomography/computed tomography [FDG-PET-CT]). Planned sample size was 35 patients (type I error, 5%; type II error, 20%). A translational substudy explored associations between response and concentration of circulating angiogenic factors. Results. Futility analysis was performed after 21 patients (11 female, mean age 67 years; liposarcoma n = 15); 17/21 patients were evaluable for the primary endpoint. The MRR was 1/17 (5.9%, 95% confidence interval \ 0.01-0.29). Mean change in SUV mean of post-versus pretreatment PET was a 6% decrease (range 65% decrease to 34% increase); 7/21 (33.3%) patients had 12 grade 3/4 toxicities, and 19/21 (95.2%) patients were resected (all R0). One (4.8%) patient suffered a grade 4 postoperative complication (anastomotic leakage). Circulating endothelial progenitor cells, soluble vascular endothelial growth factor, and angiopoietin-2 concentrations showed no relevant changes during treatment. Conclusions. Although this study showed that preoperative pazopanib is not effective for unselected high-risk STS patients, relevant treatment effects were observed in a single patient. Future research needs to better define subgroups potentially benefiting from preoperative pazopanib treatment. ClinicalTrials.gov identifier. NCT01543802.
Efficacy of Pazopanib in Patients with Pretreated Advanced Stage Soft Tissue Sarcomas
Acta Oncologica Turcica
Background: Pazopanib acts as a multitargeted tyrosine kinase inhibitor. It has been shown to be effective in patients with advanced stage Soft Tissue Sarcomas (STSs). We aimed to evaluate survival times and significant side effects by making a retrospective evaluation of real-life data. Materials and Methods: This study was carried out with a retrospective method. Clinical characteristics of adult patients with advanced STSs treated with the pazopanib were recorded in the hospital's patient registry database. Patients without medical records were excluded from the study. Objective response rate (ORR), Progression-free survival (PFS), overall survival (OS), and treatmentrelated pneumothorax and hypertension side effects were determined. Results: Forty adult patients were included (males: 55%). The median age was 44.5 years (range: 20-88). Malignant mesenchymal tumor by histopathology was found in 32.5% of the sample. Eighty-eight percent of the sample had a Stage 3 or higher disease at the time of initial diagnosis. Seventy percent of the patients had lung metastases. Seventy percent of the patients received two or more lines of systemic chemotherapy prior to pazopanib. The ORR to the pazopanib was 45% for whole patients. Median PFS (IQR) was determined as 5.73 (2.67) months (95% Confidence Interval (CI) of 5.19 to 6.19 months). Median OS (IQR) was 8.54 (17.81) months (95% CI of 8.24 to 15.65 months). Pneumothorax was detected during pazopanib in twelve and a half percent of patients. Hypertension was detected during pazopanib in fifteen percent of patients. Conclusion: Pazopanib led to significant survival in this pretreated population of patients based on reallife data. It also has a manageable side-effect profile.
Real-World Outcome and Prognostic Factors of Pazopanib in Advanced Soft Tissue Sarcoma
Cancer Management and Research
Purpose: Pazopanib has been approved for treating soft tissue sarcomas (STS) after chemotherapy. We aimed to evaluate the prognostic factors, clinical outcomes, and tolerability of pazopanib in patients with STS. Patients and Methods: Forty-five patients treated between June 2015 and August 2019 were reviewed. Clinical outcome was measured by assessing the disease control rate (DCR) using Response Evaluation Criteria in Solid Tumors (version 1.1). Progression-free survival (PFS) and overall survival (OS) were estimated using the Kaplan-Meier method. Adverse effects were assessed using the Common Terminology Criteria for Adverse Events (version 5.0). Results: The median age of patients at diagnosis was 28 (interquartile range (IQR), 23-45) years. Pazopanib was used as the second-line treatment in 46.7% and the subsequent line in 53.3% of patients. The overall DCR was 55.6%, and at 8 and 12 weeks, it was 52.3% and 35.5%, respectively; the median duration of response was 7 (IQR: 2-18) months. Pazopanibinduced hypothyroidism was associated with DCR, with an odds ratio of 7 (95% confidence interval [95% CI: 1.7-27.5], p<0.01). The median PFS and OS were 4.1 (95% CI: 0.85-7.42) and 12.4 months (95% CI: 6.5-18.36), respectively. Hypothyroidism and response to pazopanib, better ECOG PS, histological subtypes desmoid tumor/aggressive fibromatosis (DT/ AF), and alveolar soft part sarcoma (ASPS) were favorable prognostic factors for PFS. Hypothyroidism and response to pazopanib were significant favorable factors for OS. There was no statistical difference in the OS between patients using pazopanib as the second-line therapy and those using it as the subsequent-line therapy. Conclusion: Pazopanib is an effective treatment for STS. However, it showed variability in the clinical outcome in favor of ASPS and an outstanding response in the DF/AT subtype. Pazopanib-induced hypothyroidism is a good prognostic factor for disease control and is associated with prolonged PFS and OS.
Molecular and Clinical Oncology, 2014
Soft tissue sarcomas (STS) are a group of rare mesenchymal cancers that include approximately 50 histological types and account for 1% of all adult cancers. The standard curative treatment option for localized disease is surgical resection and, if a surgically removed tumor exhibits high-risk characteristics, adjuvant chemotherapy and radiotherapy may be administered. Sarcoma presenting at an advanced stage has a dismal prognosis and survival has not markedly improved over the last 20 years. The standard first-line treatment for advanced STS, other than gastrointestinal stromal tumors, is cytotoxic chemotherapy. Therapies targeting pro-angiogenic factors have been a focus of drug development for STS over the last few years. Pazopanib, a multitargeted tyrosine kinase inhibitor, is a novel treatment option for patients with metastatic STS in the second-line setting. This is a presentation of 2 case reports of patients with metastatic STS who responded well to treatment with pazopanib.
BMC Cancer, 2019
Background: PALETTE 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. Methods: PALETTE 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. Results: A 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. Conclusions: Longer 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 registration: NCT00753688, first posted September 16, 2008 (registered prospectively).