crizotinib and Sarcoma--Alveolar-Soft-Part

Alveolar soft part sarcoma (ASPS) is an orphan malignancy associated with a rearrangement of transcription factor E3 (TFE3), leading to abnormal MET gene expression. We prospectively assessed the efficacy and safety of the MET tyrosine kinase inhibitor crizotinib in patients with advanced or metastatic ASPS.. Eligible patients with reference pathology-confirmed ASPS received oral crizotinib 250 mg bd. By assessing the presence or absence of a TFE3 rearrangement, patients were attributed to MET+ and MET- sub-cohorts. The primary end point was the objective response rate (ORR) according to local investigator. Secondary end points included duration of response, disease control rate (DCR), progression-free survival (PFS), progression-free rate, overall survival (OS) and safety.. Among 53 consenting patients, all had a centrally confirmed ASPS and 48 were treated. A total of 45 were eligible, treated and assessable. Among 40 MET+ patients, 1 achieved a confirmed partial response (PR) that lasted 215 days and 35 had stable disease (SD) as best response (ORR: 2.5%, 95% CI 0.6% to 80.6%). Further efficacy end points in MET+ cases were DCR: 90.0% (95% CI 76.3% to 97.2%), 1-year PFS rate: 37.5% (95% CI 22.9% to 52.1%) and 1-year OS rate: 97.4% (95% CI 82.8% to 99.6%). Among 4 MET- patients, 1 achieved a PR that lasted 801 days and 3 had SD (ORR: 25.0%, 95% CI 0.6% to 80.6%) for a DCR of 100% (95% CI 39.8% to 100.0%). The 1-year PFS rate in MET- cases was 50% (95% CI 5.8% to 84.5%) and the 1-year OS rate was 75% (95% CI 12.8% to 96.1%). One patient with unknown MET status due to technical failure achieved SD but stopped treatment due to progression after 17 cycles. The most common crizotinib-related adverse events were nausea [34/48 (70.8%)], vomiting [22/48 (45.8%)], blurred vision [22/48 (45.8%)], diarrhoea (20/48 (41.7%)] and fatigue [19/48 (39.6%)].. According to European Organization for Research and Treatment of Cancer (EORTC) efficacy criteria for soft tissue sarcoma, our study demonstrated that crizotinib has activity in TFE3 rearranged ASPS MET+ patients.. EORTC 90101, NCT01524926.

Topics: Adolescent; Adult; Aged; Antineoplastic Agents; Basic Helix-Loop-Helix Leucine Zipper Transcription Factors; Crizotinib; Female; Gene Rearrangement; Humans; Male; Middle Aged; Progression-Free Survival; Protein Kinase Inhibitors; Sarcoma, Alveolar Soft Part; Young Adult

Topics: Basic Helix-Loop-Helix Leucine Zipper Transcription Factors; Crizotinib; Humans; Sarcoma, Alveolar Soft Part; Soft Tissue Neoplasms; Translocation, Genetic; Tumor Microenvironment

Alveolar Soft Part Sarcoma (ASPS) is a rare, slow-growing, but highly vascular soft tissue sarcoma, characterised by a high rate of metastases at presentation. Although imaging features of the primary are well described, less detail is available on the imaging pattern of metastatic ASPS. The EORTC 90101 (CREATE) study assessed the efficacy of Crizotinib in patients with metastatic ASPS and presents a unique opportunity to describe the imaging phenotype of primary and metastatic ASPS, based on prospectively collected imaging.. A retrospective review of the staging CT scans of 32 patients with ASPS from the CREATE study was undertaken and the imaging features of primary and metastatic disease were assessed.. Imaging of the primary tumour was available in 7/32 cases (28%). All primary tumours demonstrated marked vascularity with prominent feeding vessels (7/7, 100%). The most frequent sites of metastases included lung (30/32, 94%), nodal (7/32, 22%), bone (5/32, 16%) and muscle/subcutaneous (5/32, 16%). Features of hypervascularity were identified at all sites, more appreciable in the lungs, with feeding vessels frequently demonstrated in pulmonary metastases (21/32, 66%).. Analysis of imaging from the CREATE cohort of patients with metastatic ASPS demonstrates that metastases from ASPS are predominantly hypervascular and demonstrate feeding vessels comparable to primary ASPS, suggesting potential sensitivity of this rare sarcoma for antivascular/antiangiogenic treatment approaches.

Topics: Adult; Antineoplastic Agents; Crizotinib; Female; Humans; Lung Neoplasms; Male; Sarcoma, Alveolar Soft Part; Soft Tissue Neoplasms; Tomography, X-Ray Computed