In a precision medicine success story, crizotinib (Xalkori) demonstrated a 50% objective response rate and a 100% disease control rate in patients with <em>ALK</em>-positive advanced, inoperable inflammatory tumors, in findings from the CREATE study presented at the 2018 AACR Annual Meeting.
Patrick Schöffski, MD, MPH
Patients withALK-positive advanced, inoperable inflammatory myofibroblastic tumors (IMTs) who were treated with crizotinib (Xalkori), an ALK inhibitor, demonstrated an objective response rate (ORR) of 50% (95% CI, 21.1%-78.9%) and a disease control rate (DCR) for crizotinib of 100% (95% CI, 73.5%-100.0%), according to findings from a phase II trial that were presented during the 2018 AACR Annual Meeting.1
Results from the EORTC 90101 trial, also known as the CREATE study, were simultaneously published in The Lancet Respiratory Medicine,2showing that of the 12 evaluable patients withALK-positive IMT, 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).
"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 theNew England Journal of Medicine,3the NCCN guidelines incorporated crizotinib as a category 2A recommendation forALK-positive IMT in 2012. Findings for pediatric patients with IMT were published inThe Lancet Oncologyin 2013 and more recently, in 2017, in the Journal of Clinical Oncology.4,5Both reports demonstrated responses with crizotinib for pediatric patients withALK-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 withALK-positive inflammatory myofibroblastic tumor who cannot be treated with surgery," Schöffski said.
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 wasALK-positive (n = 12; ≥15% expression by FISH or immunohistochemistry) orALK-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.
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 withALK-positive IMT, the median age was 35.5 years (range, 21-69). Fifty percent of patients in theALK-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 withALK-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 withALK-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 withALK-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 theALK-positive and -negative groups,” Schöffski noted.
Crizotinib was initially granted an accelerated approval for the treatment of patients withALK-positive nonsmall 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 withROS1-positive NSCLC in 2016.