Although the European Organization for Research and Treatment of Cancer 90101 CREATE study fell short of its primary endpoint, it demonstrated the activity of crizotinib (Xalkori) in patients with advanced or metastatic alveolar soft part sarcoma in key secondary endpoints.
Sir Richard Peto, FRS
Although the European Organization for Research and Treatment of Cancer (EORTC) 90101 CREATE study fell short of its primary endpoint, it demonstrated the activity of crizotinib (Xalkori) in patients with advanced or metastatic alveolar soft part sarcoma (ASPS) in key secondary endpoints.
The multicenter, single-agent, non-randomized, open-label, 2-staged phase II trial is 1 of the first ASPS-specific prospective studies. The study evaluated the efficacy and safety of crizotinib in patients with locally advanced or metastatic ASPS who were deemed incurable by conventional surgery, radiotherapy, or systemic therapy.
In addition to the independent ASPS cohort, CREATE included 6 disease-specific groups to evaluate the efficacy and safety of crizotinib in patients with locally advanced or metastatic tumors driven byMETand/orALKalterations. Other diseases included anaplastic large cell lymphoma, inflammatory myofibroblastic tumor, papillary renal cell carcinoma type 1, clear cell sarcoma, and alveolar rhabdomyosarcoma.
“This is probably the largest prospective series in the literature,” said lead author, Patrick Shöffski, MD, MPH, of the University Hospitals Leuven, Belgium, in a statement. “Due to the long follow-up of these patients, the PFS, OS, and other important parameters, which are not usually covered by early phase II trials, could be reported.”
Forty-eight patients were enrolled in the study, 45 of which were evaluable for efficacy. Patients were stratified intoMETaltered (MET+)(n = 40) or nonMETaltered (MET-)(n = 4) sub-cohorts on the basis of the presence or absence of aTFE3gene rearrangement, assessed by fluorescence in situ hybridization (FISH). One patient had questionable MET status and was assessed separately.
The median age of the treated patients was 30. The majority of patients (75%) had an ECOG performance status of 1. Most patients (64.6%) had undergone prior surgery and 47.9% had received prior systemic therapy.
All patients were treated with oral crizotinib at a starting dose of 250 mg twice daily. One treatment cycle was defined as 21 days.
The primary endpoint was objective response rate (ORR) per RECIST 1.1 with response confirmation, assessed by the local investigator. Secondary endpoints included progression-free response rate (PFS), overall survival (OS), duration of response (DOR), disease control rate (DCR), complete response (CR), partial response (PR), and safety.
The study was deemed to be positive if more than 6 of 35 patients withMET+ASPS responded in the second stage. Treatment activity of crizotinib in the study population was declared if the ORR was greater than 10%.
Among 40MET+patients, 1 achieved a confirmed partial response (PR) for 215 days and 35 patients had stable disease (SD) as best response (ORR, 2.5%; 95% CI, 0.6-80.6%). The DCR was 90% (95% CI, 76.3-97.2%). The 1-year PFS rate was 37.5% (95% CI, 22.9-52.1%) and the 1-year OS rate was 97.4% (95% CI, 82.8-99.6%). At 2 years, the OS rate was 81.3% (95% CI, 64.7%-90.6%). The DOR was 215 days in responding patients.
Among 4MET-patients, 1 achieved a PR for 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 was 50% (95% CI, 5.8%-84.5%) and the 1-year OS rate was 75% (95% CI, 12.8%-96.1%). The DOR was 801 days in responding patients. The 1 patient with questionableMETstatus achieved stable disease.
The median relative dose intensity for both sub-cohorts was 98.2% with 27 out of the 45 patients requiring dose reductions or dose modifications. The treatment duration with crizotinib ranged from 2.4 to 156.1 weeks. After a median follow-up of 833 days, 2 patients were still receiving treatment with crizotinib.
No new safety signals were detected in patients with ASPS compared with the safety profile from previous studies of crizotinib. The most common crizotinib-related adverse events were nausea, vomiting, blurred vision, diarrhea, and fatigue. No deaths occurred on treatment or within 4 weeks of treatment discontinuation.
The primary endpoint of the trial was not met because at least 2 objective and radiologically confirmed responses by RECIST 1.1 criteria were not observed among the first 12MET+patients in stage 1, representing the limitations of using response rates in early clinical trials. However, durable responses were noted in secondary endpoints, such as PFS and OS.
Furthermore, based on the EORTC criteria for soft tissue sarcoma, the study demonstrted that crizotinib was active inTFE3-rearranged patients withMET+ASPS. Long-term follow-up of this trial will serve as an important reference for all future clinical studies in this setting, Shöffski et al suggested.
CREATE is among several completed and ongoing trials evaluating the role of novel targeted therapies in ASPS. Other targeted therapies under evaluation in ASPS include pazopanib (Votrient; NCT021133826) and sunitinib (Sutent; NCT01391962).
P Schöffski, A Wozniak, B Kasper, et al. 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 II trial 90101 “CREATE” [published online December 5, 2017]. Annals of Oncology. doi: 10.1093/annoc/mdx774.