EORTC 90101 “CREATE” phase II trial on the activity and safety of crizotinib in patients with alveolar soft part sarcoma (ASPS) with rearrangement of TFE3 is published in the Annals of Oncology. EORTC 90101 “CREATE” is a multi-tumor, prospective phase II clinical trial evaluating the efficacy and safety of crizotinib in patients with advanced tumors driven by MET and/or ALK alterations. CREATE included six disease-specific groups, and this paper reports on the results of the independent ASPS cohort.

ASPS is a rare soft-tissue sarcoma (STS), generally developing in young patients. This disease is characterized by very early metastatic spread. ASPS is known to metastasize to sites, such as the brain, lung, lymph nodes, and bones. In patients with advanced, inoperable, or metastatic disease, traditional systemic therapy and radiotherapy have failed to demonstrate significant advantages in survival.

The tumor is characterized by the ASPSCR1-TFE3 fusion gene, which plays a critical role in the development of ASPS as it induces an overexpression of the MET gene that encodes the MET receptor tyrosine kinase, which is considered to be an important driver of this disease. Crizotinib (Xalkori®, Pfizer Inc.) is a small molecule targeting MET, anaplastic lymphoma kinase (ALK), and ROS proto-oncogene-1 receptor tyrosine kinase (ROS1). The drug is routinely used in adult patients with non-small-cell lung cancer. Its mechanism of action is to interfere with the MET pathway by inhibiting adenosine triphosphate (ATP) from binding to the receptor.

In this study, 53 patients were enrolled, of which 45 patients were eligible. The patients were stratified to MET+ or MET- groups and treated with oral crizotinib at a dose of 250 mg twice daily. Among 40 MET+ patients, one achieved a confirmed partial response for 215 days and 35 patients had stable disease (SD). Further efficacy endpoints in MET+ cases were a disease control rate of 90.0%, a 1-year progression-free survival rate of 37.5%, and a 1-year overall survival rate rate of 97.4%.

The most common crizotinib-related adverse events were nausea, vomiting, blurred vision, diarrhea, and fatigue. The study demonstrated that crizotinib was active in TFE3 rearranged ASPS patients, when considering standard efficacy endpoints for early sarcoma trials developed by EORTC.

“In terms of number of treated patients, this is the largest prospective trial ever performed in ASPS,” said Professor Patrick Schöffski, Principal Investigator and Head of Department of General Medical Oncology, Leuven Cancer Institute, University Hospitals Leuven. “Furthermore, I think that the long-term follow-up of this trial, with very mature overall survival data, will serve as an important reference for all future clinical studies in this setting.”