Activity and safety of crizotinib in patients with alveolar soft part sarcoma with rearrangement of TFE3 . European Organization for Research and Treatment of Cancer (EORTC) phase 2 trial 90101 “CREATE”

Abstract

Background

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 tyrosine kinase inhibitor(TKI) crizotinib in patients with advanced or metastatic ASPS.

Patients and methods

Eligible patients with reference pathology-confirmed ASPS received oral crizotinib 250 mg twice daily. By assessing the presence or absence of a TFE3 rearrangement, patients were attributed to MET+ and MET- sub-cohorts. The primary endpoint was the objective response rate(ORR) according to local investigator. Secondary endpoints included duration of response(DOR), disease control rate(DCR), progression-free survival(PFS), progression-free rate(PFR), overall survival(OS) and safety.

Results

Among 53 consenting patients, all had a centrally confirmed ASPS and 48 were treated. A total of 45 were eligible, treated and evaluable. Among 40 MET+ patients, 1 achieved a confirmed PR that lasted 215 days and 35 had stable disease(SD) as best response(ORR:2.5%, 95%CI:0.6-80.6%). Further efficacy endpoints in MET+ cases were DCR:90.0%(95%CI:76.3-97.2%), 1-year PFS rate: 37.5%(95%CI:22.9-52.1%) and 1-year OS rate:97.4%(95%CI:82.8-99.6%). Among 4 MET- patients, 1 achieved a PR that lasted 801 days and 3 had SD(ORR:25.0%,95%CI:0.6-80.6%) for a DCR of 100% (95%CI:39.8-100.0%). The 1 year PFS rate in MET- cases was 50%(95%CI:5.8-84.5%) and the 1-year OS rate was 75%(95%CI:12.8-96.1%). 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%]).

Conclusion

According to EORTC efficacy criteria for soft tissue sarcoma, our study demonstrated that crizotinib has activity in TFE3 rearranged ASPS MET+ patients.

Clinical trial number

EORTC 90101, NCT01524926