Publication of EORTC 90101 “CREATE” Phase II trial

Results of the EORTC 90101 “CREATE” Phase II trial were published in the Annals of Oncology journal. The study ^(*) measured the activity and safety of the tyrosine kinase inhibitor (TKI) crizotinib in advanced clear cell sarcoma patients with MET alterations.

Clear cell sarcoma of soft tissue (CCSA) is a rare type of cancer primarily affecting young adults between 20 to 40 years old. It is a translocation-associated sarcoma, which means that mutations define the disease. In chromosomal translocations, the sections of two chromosomes are interchanged, which can result in an abnormal fusion of genes. Hence, CCSA is characterised by a specific t(12;22) translocation, that rearranges the EWSR1 gene and leads to overexpression of MET.

In the EORTC 90101 “CREATE” study, 28 eligible patients received oral crizotinib 250 mg twice daily. Primary endpoint was objective response rate (ORR), secondary endpoints included duration of response, disease control rate (DCR), progression-free survival (PFS), progression-free rate (PFR), overall survival (OS), overall survival rate (OSR) and safety.

The results showed that 26 out of 28 patients had MET+ disease, one patient achieved a confirmed partial response and 17 patients had stable disease. Further efficacy endpoints in MET+ CCSA were DCR of 69.2%, median PFS of 131 days, median OS of 277 days. The 3, 6, 12 and 24 month PFR was 53.8%, 26.9%, 7.7% and 7.7%, respectively. Among two evaluable MET– patients, one had stable disease and one had progression. The most common treatment-related adverse events were nausea, fatigue, vomiting, diarrhea, constipation and blurred vision. The study surmised that the progression free rate with crizotinib in MET+ CCSA is similar to results achieved in first-line with the single-agent, doxorubicin in patients with metastatic soft tissue sarcomas. In further lines for previously treated sarcoma patients, the PFS is similar to pazopanib. The phase 2 trial demonstrated that crizotinib provided clinical benefit for CCSA cases with documented EWSR1 gene rearrangement, achieving disease control for a median of 131 days.

“We not only studied an interesting targeted agent in such a precision medicine trial in this orphan disease” says Professor Patrick Schöffski, leading author of the study and Head of General Medical Oncology Department at the Leuven Cancer Institute, “but that it also describes the natural course of this very rare disease in a prospective fashion”.

“This is probably the largest prospective series in the literature”, Schöffski reflected. “Due to the long follow-up of these patients, the PFS, OS and other important parameters (which are usually not covered by early Phase 2 trials) could be reported”.

“This paper will be a scientific basis for future clinical research in the field of clear cell sarcoma”, he concluded.

*There are six independent disease specific cohorts of this trial, this paper summarised the key findings of one of the cohorts; other papers are submitted or in preparation.