Long-term efficacy update of crizotinib in patients with advanced, inoperable inflammatory myofibroblastic tumour from EORTC trial 90101 CREATE

Abstract

Purpose: European Organisation for Research and Treatment of Cancer (EORTC) 90101 (CREATE) was a prospective, multicentric, non-randomised, open-label phase II basket trial to assess the efficacy and safety of crizotinib in patients with different types of cancers, including advanced inflammatory myofibroblastic tumour (IMT) with or without anaplastic lymphoma kinase (ALK) rearrangements. Here, we report updated results with long-term follow-up. Patients/methods: After central reference pathology, eligible ALK-positive and ALK-negative patients with advanced/metastatic IMT deemed incurable with surgery, radiotherapy or systemic therapy received oral crizotinib 250 mg twice daily. The ALK status was assessed centrally using immunohistochemistry and fluorescence in situ hybridisation. The primary endpoint was the proportion of patients who achieved an objective response (i.e. complete or partial response). If 6 ALK-positive patients achieved a confirmed response, the trial would be deemed successful. Results: At data cut-off on 28th January 2021, we performed the final analysis of this trial. Of the 20 eligible and treated patients (19 of whom were evaluable for efficacy), with a median follow-up of 50 months, five were still on crizotinib treatment (4/12 ALK-positive and 1/8 ALK-negative patients). The updated objective response rate (ORR) was 66.7% (95% confidence interval [CI] 34.9e90.1%) in ALK-positive patients and 14.3% (95% CI 0.0e57.9%) in ALK-negative patients. In the ALK-positive and ALK-negative patients, the median progression-free survival was 18.0 months (95% CI 4.0eNE) and 14.3 months (95% CI 1.2 e31.1), respectively; 3-year overall survival rates were 83.3% (95% CI 48.2e95.6) and 34.3% (95% CI 4.8e68.5). Safety results were consistent with previously reported data. Conclusion: These updated results confirm previous findings that crizotinib is effective, with durable responses, in patients with locally advanced or metastatic ALK-positive IMT. With further follow-up after the original primary analysis, the ORR increased, as patients derived long-term benefit and some responses converted from stable disease to partial responses. Clinical trial number: EORTC 90101, NCT01524926.

Inflammatory Myofibroblastic Tumour: State of the Art

“…In the ALK-positive group, two out of six patients showed complete response. Interestingly, a recent update analysis after a median follow-up of 50 months showed longer ORR up to 66.7% for ALK-positive patients due to the further reduction in tumor volume with long-term treatment [ 42 ]. The 12-month progression-free survival (PFS) rate was 58.3% (95% CI 27.0–80.1%) and the 12-month overall survival (OS) rate was 83.3% (95% CI (48.2–95.6%).…”

“…In the absence of large randomized studies, we must rely on published clinical cases, as well as choose treatments by analogy with the responses obtained in other cancers with the same genetic mutations. In-depth molecular characterization of archival IMT tissue from 24 patients enrolled in the CREATE trial revealed extensive molecular heterogeneity including DNA damage repair mechanisms (19/24), Wnt signaling (16/24), and cell-cycle and cell death pathway (13/24) [ 42 , 48 ]. Although the authors identified 17 potentially actionable recurrent gene aberrations including ATRX , FAT1 , FCRL4 , FOXO1 , NUTM2B , PIK3CA , SMAD4 , and TP53 , no ROS1 -rearranged tumor has been identified.…”

Case Report: Efficacy of ensartinib treatment in pulmonary inflammatory myofibroblastic tumor with a rare GCC2-ALK fusion

“…The EORTC trial 90101 CREATE clinical trial included ALK -positive and ALK- negative patients with advanced/metastatic IMT who received 250 mg of oral crizotinib twice a day; the median PFS of ALK- positive and ALK- negative patients was 18.0 months (95% CI 4.0-NE) and 14.3 months (95% CI 1.2–31.1), respectively ( 11 ). The PFS in our case was more than 11 months; however, long-term benefits still need to be observed.…”

Mesenteric inflammatory myofibroblastic tumor mimicking acute appendicitis: A case report

“…There have been recent advances in the treatment of IMTs with immunohistochemistry identifying ALK positive tumors. Such tumor have the potential of being treated with tyrosine kinase inhibitors targeting ALK which includes drugs like crizotinib and ceritinib [ 15 ].…”