The following article features coverage from the Connective Tissue Oncology Society (CTOS) 2018 meeting. Click here to read more of Cancer Therapy Advisor‘s conference coverage.

Patrick Schöffski, MD, of the Katholieke Universiteit Leuven in Belgium, presented data from what he described as the largest prospective treatment series ever performed in patients with inflammatory myofibroblastic tumors (IMFT) at the Connective Tissue Oncology Society (CTOS) 2018 Annual Meeting in Rome, Italy. During his presentation he stated that he was confident that crizotinib would be “available” to patients with this disease — suggesting that the small amount of evidence the phase 2 trial produced on the drug’s efficacy in that indication would either lead to an approval by the US Food and Drug Administration (FDA), or that it would provide sufficient evidence to support this indication and prompt sarcoma specialists to prescribe the drug off-label. Pfizer, the manufacturer of crizotinib, has already approached the FDA about a label expansion.

Because IMFT is an orphan malignancy it is not possible to conduct larger randomized trials; it took investigators from the University Hospitals Leuven in Belgium 61 months across 13 sites in 8 European countries to find 35 patients with a local diagnosis of IMFT that could be considered for the trial. During the enrollment process it was uncovered that some of these patients were not diagnosed correctly — there was a local misclassification rate of 31.4% — so many patients originally thought to be eligible were eliminated from the analysis.

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The results from the CREATE trial were first published in April 2018 in The Lancet Respiratory Medicine, and followed a move by the US National Comprehensive Cancer Network (NCCN) in 2012 to recommend the treatment for IMFT based on a single patient with an ALK rearrangement from a phase 1 trial.2 It’s not entirely unprecedented for the FDA to consider a drug for this indication based on such small amounts of evidence — according to Dr Schöffski, the results from the phase 2 study likely represent “the best type of evidence that can be generated in this indication.”

The phase 2 trial enrolled 19 evaluable patients into the multicenter, biomarker-driven, nonrandomized trial, and patients were divided into 2 subgroups: ALK-rearranged and not rearranged (ALK+ and ALK-, respectively). There were 12 ALK+ patients and 7 ALK– patients.

Half of the ALK+ patients were found to respond to the drug; 2 of those patients were deemed to show complete responses — and these complete responses were revealed following only a few months of treatment. The research group reported that 50% of ALK+ patients showed an objective response to crizotinib (95% confidence interval [CI], 21.1%-78.9%). Although all ALK+ IMFT patients saw some form of disease control with crizotinib treatment, and 81.8% are alive at 2 years after starting treatment, it is important to note that 9 patients came off the study due to disease progression.

Dr Schöffski highlighted the case of 1 ALK+ patient, who, after refusing amputation of the right leg — a procedure thought to provide curative intent — saw 29.7% shrinkage of their target lesions after 16 treatment cycles (just shy of 1 year of treatment) with crizotinib.

Curiously, there was 1 ALK– patient in the trial who saw an almost complete response. Dr Schöffski provided some possible reasons for why this occurred, saying that perhaps the patient was really ALK+, but the assay used to measure this status may not have captured the alteration or could have produced a false negative. IMFT is also known to be sensitive to other genetic alterations in IMFT besides ALK, such as ROS1, the researchers hypothesized. Or, offered Dr Schöff, ALK activation could be due to point mutations instead of rearrangement, as is the case in non-small cell lung cancer.

Although no patients died as a result of treatment, there were 8 serious adverse events among 5 patients including (but not limited to) fever, pneumonia, heart attack with possible sepsis, abdominal abscess with acute renal failure, and QT prolongation.

Essentially, the research team doubled down on the suggestion they made earlier this year when they initially published their paper.

“In the absence of validated treatment alternatives for IMFT, and considering the limitations of nonrandomized drug testing, we propose to define crizotinib as the standard of care for patients with locally advanced or metastatic ALK+ IMFT,” Dr Schöffski noted at the end of his presentation.

Research from another arm of the European Organization for Research and Treatment of Cancer (EORTC) study on crizotinib in advanced, MET+ clear cell sarcoma (CCSA) was presented in a subsequent CTOS presentation, but the primary end point for that cohort was not met. The researchers who ran that trial also determined in that cohort that a EWSR1 arrangement, although found in nearly 90% of these patients, is unlikely to be a “reliable predictable biomarker of response to crizotinib.”3

Disclosure: The research for the original study lists Pfizer as a supporter.

Read more of Cancer Therapy Advisor‘s coverage of the CTOS 2018 meeting by visiting the conference page.


  1. Schöffski P, Sufliarsky J, Gelderblom H, et al. Prospective trial of crizotinib (C) in patients (PTS) with advanced, inoperable inflammatory myofibroblastic tumor (IMFT) with and without ALK alternations: EORTC phase 2 study 90101 “CREATE.” Presented at: CTOS 2018 Annual Meeting; Rome, Italy: November 14-17. Paper 017.
  2. Schöffski P, Sufliarsky J, Gelderblom H, et al. 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. Lancet Respir Med. 2018;6(6):431-441.
  3. Schöffski P, Wozniak A, Stacchiotti S, et al. Activity and safety of crizotinib in patients with advanced clear cell sarcoma (CCSA) with MET alterations. European Organization for Research and Treatment of Cancer phase 2 trial 90101 CREATE. Presented at: CTOS 2018 Annual Meeting; Rome, Italy: November 14-17. Paper 018.