Crizotinib in patients with advanced, inoperable inflammatory myofibroblastic tumours with and without anaplastic lymphoma kinase gene alterations (European Organisation for Research and Treatment of Cancer 90101 CREATE): a multicentre, single-drug, prospective, non-randomised phase 2 trial.

Background: An inflammatory myofibroblastic tumour (IMFT) is a rare mesenchymal neoplasm characterised by anaplastic lymphoma kinase (ALK) gene rearrangements. We assessed the activity and safety of crizotinib, a tyrosine kinase inhibitor, targeting ALK in patients with advanced IMFT either with or without ALK alterations.

Methods: We did a multicentre, biomarker-driven, single-drug, non-randomised, open-label, two-stage phase 2 trial (European Organisation for Research and Treatment of Cancer 90101 CREATE) at 13 study sites (five university hospitals and eight specialty clinics) in eight European countries (Belgium, France, Germany, Italy, Netherlands, Poland, Slovakia, and the UK). Eligible participants were patients aged at least 15 years with a local diagnosis of advanced or metastatic IMFT deemed incurable with surgery, radiotherapy, or systemic therapy; measurable disease; an Eastern Cooperative Oncology Group performance status of 0-2; and adequate haematological, renal, and liver function. Central reference pathology was done for confirmation of the diagnosis, and ALK positivity or negativity was assessed centrally using immunohistochemistry and fluorescence in-situ hybridisation based on archival tumour tissue and defined as ALK immunopositivity or rearrangements in at least 15% of tumour cells. Eligible ALK-positive and ALK-negative patients received oral crizotinib 250 mg twice per day administered on a continuous daily dosing schedule (the duration of each treatment cycle was 21 days) until documented disease progression, unacceptable toxicity, or patient refusal. If at least two of the first 12 eligible and assessable ALK-positive patients achieved a confirmed complete or partial response according to Response Evaluation Criteria in Solid Tumors (RECIST) 1.1, a maximum of 35 patients were to be enrolled. If at least six ALK-positive patients achieved a confirmed response, the trial would be deemed successful. The primary endpoint was the proportion of patients who achieved an objective response (ie, a complete or partial response) as per RECIST 1.1, with response confirmation assessed by the local investigator every other cycle. Activity and safety endpoints were analysed in the per-protocol population. This trial is registered with ClinicalTrials.gov, number NCT01524926.

Findings: Between Oct 3, 2012, and April 12, 2017, we recruited and treated 20 eligible participants, 19 of whom were assessable for the primary endpoint. Median follow-up was 863 days (IQR 358-1304). Six of 12 ALK-positive patients (50%, 95% CI 21·1-78·9) and one of seven ALK-negative patients (14%, 0·0-57·9) achieved an objective response. The most common treatment-related adverse events in the 20 participants were nausea (11 [55%]), fatigue (9 [45%]), blurred vision (nine [45%]), vomiting (seven [35%]), and diarrhoea (seven [35%]). Eight serious adverse events occurred in five patients: pneumonia, fever of unknown cause, a heart attack with increased creatinine and possible sepsis, an abdominal abscess with acute renal insufficiency, and a QT prolongation.

Interpretation: With 50% of participants with ALK-positive tumours achieving an objective response, crizotinib met the prespecified criteria for success in this trial. The results presented here support the rationale for inhibiting ALK in patients with IMFT. Crizotinib could be considered as the standard of care for patients with locally advanced or metastatic ALK-positive IMFT who do not qualify for curative surgery.

Funding: The European Organisation for Research and Treatment of Cancer and Pfizer.