Crizotinib Confirmed as Standard of Care for ALK+ Inflammatory Myofibroblastic Tumors

Patrick Schöffski, MD, MPH

Treatment with crizotinib (Xalkori) elicited an objective response rate (ORR) of 50% (95% CI, 21.1%-78.9%) for patients with ALK-positive advanced, inoperable inflammatory myofibroblastic tumor (IMT), according to findings from the phase II EORTC 90101 study presented at the 2018 AACR Annual Meeting and simultaneously published in The Lancet Respiratory Medicine.^1,2

In the trial, which was also known as the CREATE study, 12 patients with ALK-positive IMT were evaluable for response to crizotinib. Of these patients, 2 experienced a confirmed complete response (CR) and 4 had a confirmed partial response (PR). The remaining 6 patients had either stable disease (n = 5) or a non-confirmed PR (n = 1), for an overall disease control rate (DCR) for crizotinib of 100% (95% CI, 73.5%-100.0%).

"Inflammatory myofibroblastic tumors are usually resistant to conventional chemotherapy and radiotherapy, so patients with unresectable or locally recurring disease have few treatment options," lead investigator Patrick Schöffski, MD, MPH, head of the Department of General Medical Oncology at the Leuven Cancer Institute, University Hospitals Leuven, Belgium, said in a statement. “Our study highlights how identifying the genetic drivers of a rare type of cancer can be used to find a new precision medicine for patients who otherwise have few treatment options.”

Based on findings from a single-patient case study published in the New England Journal of Medicine,³ the NCCN guidelines incorporated crizotinib as a category 2A recommendation for ALK-positive IMT in 2012. Findings for pediatric patients with IMT were published in The Lancet Oncology in 2013 and more recently, in 2017, in the Journal of Clinical Oncology.^4,5 Both reports demonstrated responses with crizotinib for pediatric patients with ALK-positive IMT.

"Our [EORTC 90101] data in predominantly adult patients with inflammatory myofibroblastic tumors, combined with recently published data for children with this disease, support this [NCCN] recommendation and suggest that crizotinib should be considered the standard-of-care for patients with ALK-positive inflammatory myofibroblastic tumor who cannot be treated with surgery," Schöffski said.

Crizotinib was administered at 250 mg twice daily. The median age of patients in the study was 45.5 years (range, 15-78). Specifically, in those with ALK-positive IMT, the median age was 35.5 years (range, 21-69). Fifty percent of patients in the ALK-positive arm had received prior treatment. ORR was selected as the primary endpoint of the study due to a lack of data for expected progression-free survival (PFS) and overall survival (OS) rates for patients with IMT when the study was established, Schöffski noted.

At the November 9, 2017, data cutoff, 4 patients with ALK-positive IMT continued to respond to treatment with crizotinib. The median duration of response was 9.0 months. The 1-year PFS rate was 73.3% (95% CI, 37.9%-90.6%) and the 2-year PFS rate was 48.9% (95% CI, 8.8%-81.0%). Both the 1-year and 2-year OS rates were 81.8% (95% CI, 44.7%-95.1%).

In evaluable patients with ALK-negative IMT (n = 7), the ORR was 14.3% (95% CI, 0.0%-57.9%), which included 1 PR. The DCR was 85.7% (95% CI, 59.8%-100.0%), with 1 patient having progressive disease. In this group, the 1-year PFS rate was 53.6% (95% CI, 13.2%-82.5%) and the 2-year rate was 35.7% (95% CI, 5.2%-69.9%). The 1-year OS rate was 83.3% (95% CI, 27.3%-97.5%) and the 2-year rate was 62.5% (95% CI, 14.2%-89.3%). One patient was not evaluable, as they did not have measurable disease at baseline.

The most common adverse events (AEs) related to crizotinib in the study were nausea (55%), fatigue (45%), blurred vision (45%), vomiting (35%), and diarrhea (35%). There were 8 serious AEs experienced by 5 patients, namely 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. Only 1 patient discontinued therapy due to toxicity.

“The inclusion in our trial of a group of patients with ALK-negative inflammatory myofibroblastic tumors provides valuable insight into the selectivity of crizotinib and our understanding of this rare disease, even if we cannot formally compare the outcomes for the ALK-positive and -negative groups,” Schöffski noted.

Crizotinib was initially granted an accelerated approval for the treatment of patients with ALK-positive non—small cell lung cancer (NSCLC) in 2011. This was followed by a full regulatory approval for this indication in 2013. The agent was also approved for patients with ROS1-positive NSCLC in 2016.

References:

1. Schoffski P, Sufliarsky J, Gelderblom H, et al. Prospective precision medicine trial of crizotinib (C) in patients (pts) with advanced, inoperable inflammatory myofibroblastic tumor (IMFT) with and without ALK alterations: EORTC phase II study 90101 "CREATE". Presented at: American Association for Cancer Research Annual Meeting, April 14-18, 2018, Chicago, Illinois. Abstract CT045.
2. Schoffski 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 [published online April 15, 2018]. Lancet Respir Med. doi: 10.1016/S2213-2600(18)30116-4
3. Butrynski JE, D'Adamo DR, Hornick JL, et al. Crizotinib in ALK rearranged inflammatory myofibroblastic tumor. N Engl J Med. 2010 Oct 28;363(18):1727-3
4. Mossé YP, Lim MS, Voss SD, et al. Safety and activity of crizotinib for paediatric patients with refractory solid tumours or anaplastic large-cell lymphoma: a Children's Oncology Group phase 1 consortium study. Lancet Oncol. 2013 May;14(6):472-80.
5. Mossé YP, Voss SD, Lim MS, et al. Targeting ALK With Crizotinib in Pediatric Anaplastic Large Cell Lymphoma and Inflammatory Myofibroblastic Tumor: A Children's Oncology Group Study. J Clin Oncol. 2017;35(28):3215-3221.

<<< 2018 AACR Annual Meeting

The EORTC 90101 study enrolled 20 patients with IMT, which is a rare soft tissue sarcoma, across 8 European countries between 2012 and 2017. Patients enrolled in the study could have either IMT that was ALK-positive (n = 12; ≥15% expression by FISH or immunohistochemistry) or ALK-negative (n = 8). The primary endpoint assessed ORR in the first 12 patients enrolled, with a response rate of 50% of greater deemed as success.